CN102197031A - Substituted 5-aminopyrazoles and use thereof - Google Patents
Substituted 5-aminopyrazoles and use thereof Download PDFInfo
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- CN102197031A CN102197031A CN2009801418695A CN200980141869A CN102197031A CN 102197031 A CN102197031 A CN 102197031A CN 2009801418695 A CN2009801418695 A CN 2009801418695A CN 200980141869 A CN200980141869 A CN 200980141869A CN 102197031 A CN102197031 A CN 102197031A
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- 0 CC1C(C)C(CCNC(**)=IC)*C2C1C2 Chemical compound CC1C(C)C(CCNC(**)=IC)*C2C1C2 0.000 description 20
- KVZJLSYJROEPSQ-UHFFFAOYSA-N CC1C(C)CCCC1 Chemical compound CC1C(C)CCCC1 KVZJLSYJROEPSQ-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The present application relates to novel substituted 5-aminopyrazoles, methods of production thereof, use thereof alone or in combinations for the treatment and/or prophylaxis of diseases and use thereof for the production of medicinal products for the treatment and/or prophylaxis of diseases.
Description
The application relate to new substituted 5-amino-pyrazol, its manufacture method, it is alone or in conjunction with being used for the treatment of and/or prophylactic purposes and be used to make the purposes that treats and/or prevents the medicine that disease uses.
Adenosine (a kind of purine nucleoside) is present in all cells and discharges under the effect that many physiology and physiopathology stimulate.Forming adenosine in the degradation process of adenosine-5'-phosplate (AMP) and S-adenosyl homocysteine also can or discharge from cell after cell damage via transhipment.Also can produce the extracellular adenosine via the nucletidase catalyzed degradation of adenine nucleotide.Subsequently, by being attached on the specific receptors, the adenosine that has discharged plays the effect of hormone like substance or neurotransmitter.But the concentration of extracellular adenosine significantly fluctuates and depends on stress level in organ and the particular organization.Therefore, in ischemic or anoxic illness, the EC of adenosine significantly improves.Subsequently, adenosine has cytoprotection usually, the metabolism that for example increases oxygen supply or slow down relevant organ.
By the effect of specific receptors mediation adenosine, described specific receptors is subdivided into hitherto known four kinds of hypotype: A1, A2a, A2b and A3.These acceptors belong to g protein coupled receptor family, and it is a feature with seven membrane spaning domains.And A1 and A3 acceptor are coupled on the Gi-albumen, the reduction that this suppresses adenylate cyclase and therefore causes cAMP content in the cell, and A2a and A2b acceptor are via Gs-protein activation adenylate cyclase, and this causes, and cAMP increases in the cell.Adenosine Receptors also can be coupled to other signal transduction system, for example on the Phospholipase C.Therefore, the activation of A1 acceptor also can cause the stimulation of potassium channel or the inhibition of calcium channel.
According to the present invention, " Adenosine Receptors-selective ligands " is meant and is selectively bound to the material that also imitates the effect (adenosine agonists) of adenosine in doing so on one or more Adenosine Receptors hypotypes or block its effect (adenosine antagonist).
Can measure above-mentioned receptor-selective to the effect of clone by these materials; It expresses receptor subtype (Olah M.E separately after with corresponding cDNA stable transfection; Ren H.; Ostrowski J.; Jacobson K.A. and Stiles G.L.:Cloning; Expression; And characterization of the unique bovine A1 adenosine receptor. Studies on the ligand binding site by site-directed mutagenesisJ. Biol. Chem.1992,267,10764-10770, its disclosure is incorporated herein by this reference in full).
Can detect effect (the Klotz N. of these materials by the biological chemistry measurement of courier cAMP in the cell to this type of clone, Hessling J., Hegler J., Owman C., Kull B., Fredholm B.B. and Lohse J.M.:Comparative pharmacology of human adenosine receptor subtypes-characterization of stably transfected receptors in CHO cells.
Naunyn Schmiedebergs Arch. Pharmacol.1998,357,1-9, its disclosure is incorporated herein by this reference in full).
Provide the broad-spectrum curing potentiality with the selectivity interaction of Adenosine Receptors hypotype, for example, the adjusting of heart rate, convergent force and blood pressure, renal function and respiratory system in the cardiovascular systems, immune adjusting and to effect (the Jacobson K.A and the Gao Z. of some functions of central nervous system and cell growth, Adenosin receptors as therapeutic targets
Nature Reviews Drug Discovery2006,5,247-264).
Adenosine A 1 receptor is strongly expressed in brain (for example cortex, hippocampus), but also is expressed in peripheral organ and tissue, in heart, kidney, lung or adipocyte.
In kidney, adenosine A 1 receptor participates in the control of body fluid and electrolyte balance fatefully.In the glomeruli of pronephros microcirculation, in renal glomerulus, in juxtaglomerular apparatus and in collection tube and medullary loop, express the A1 acceptor.The activation of A1 acceptor causes glomerular filtration rate(GFR and kidney blood flow to descend in the kidney.By the vasoconstriction of afferent arteriole and by the inhibition of the pipe ball Feedback mechanism of mainly the automatic adjusting of renal glomerulus vascular resistance being responsible for (TGF) cause these effects (Welch J.W.,
Current Opinion in Pharmacology2002,2,165-170).
Show that in various zooscopies and people's clinical trial suppressing the A1 acceptor by selectivity A1 antagonist is that uricosuric is drained, urgees natruresis and stayed the potassium diuresis.In addition, glomerular filtration rate(GFR is not subjected to adenosine A 1 receptor antagonists to influence (Vallon V., Miracle C. and Thomson S., Adenosine and kidney function:potential implications in patients with heart failure
Eur. J. Heart Failure2008,10,176-187).In the various animal models of acute and chronic renal failure, also can show the kidney provide protection of A1 antagonist by keeping glomerular filtration rate(GFR and renal plasma flow to bring into play (Welch J.W.,
Current Opinion in Pharmacology2002,2,165-170; Nagashima K., Kusaka H. and Karasawa A., Protective effects of KW-3902, an adenosine A1 receptor antagonist, against cisplatin-induced acute renal failure in rats.
Jpn. J. Pharmacol.1995,67,349-357; Kalk P., Eggert B., Relle K., Godes M., Heiden S., Sharkovska Y., Fischer Y., Ziegler D., Bielenberg G.W. and Hocher B.:The denosine A1 receptor antagonist SLV 320 reduces myocardial fibrosis in rats with 5/6 nephrectomy without affecting blood pressure.
Brit. J. Pharmacol.2007,151,1025-1032).
In heart failure patient, usually observe the decline of renal function.Treatment is to use the medullary loop hydragog(ue), furosemide for example, but this causes glomerular filtration rate(GFR to descend and therefore causes not desirable complication of the illness of heart failure patient.In addition, the diuretic(s) opposing is another indication of the poor prognosis of heart failure patient.
Therefore selectivity A1 antagonist especially is fit to acute decompensated heart failure of treatment and chronic heart failure.In addition, they can be used for ephrosis and other nephropathy, the kidney protection in for example acute and chronic renal failure and the chronic renal insufficiency.
The 5-amino-pyrazol of the replacement of the various kinds that are used for the treatment of diabetes is disclosed in WO 2004/050651, WO 2005/086656, WO 2005/112923 and WO 2007/027842.WO 93/19054 has described the arylamino pyrazoles as mycocide.The pyridyloxy pyrazoles is proposed as weedicide in JP 07-285962.WO 2008/008286 discloses substituted pyrazolecarboxylic as the ghrelin receptor antagonist that is used for the treatment of obesity.
The problem that the present invention faces provides strong and selective antagonist that serves as adenosine A 1 receptor and the novel cpd that therefore is applicable to disease treatment and/or prevention.
The present invention relates to the compound of general formula (I) and the solvate of their salt, solvate and this salt
Wherein
Q represents phenyl or pyridyl,
R
1Represent hydrogen, cyano group, (C
1-C
3)-alkyl, trifluoromethyl, (C
1-C
3)-alkoxyl group or trifluoromethoxy,
R
2Represent phenyl, naphthyl or 5-or 6-unit heteroaryl,
Wherein phenyl, naphthyl and 5-or 6-unit heteroaryl can be independently from each other halogen, cyano group, (C by 1 or 2
1-C
4)-alkyl, single methyl fluoride, difluoromethyl, trifluoromethyl, (C
1-C
4The substituting group of)-alkoxyl group, single fluorine methoxyl group, difluoro-methoxy and trifluoromethoxy replaces,
R
3Representation hydroxy carbonyl, aminocarboxyl, cyano group aminocarboxyl, (C
1-C
4)-alkyl sulfonyl-amino carbonyl,
Bisoxazoline ketone group (oxadiazolonyl) or tetrazolium-5-base,
Wherein
Bisoxazoline ketone group (oxadiazolonyl) can be replaced by methyl substituents,
R
4Represent hydrogen, halogen, (C
1-C
4)-alkyl, single methyl fluoride, difluoromethyl, trifluoromethyl, (C
1-C
4)-alkoxyl group, single fluorine methoxyl group, difluoro-methoxy or trifluoromethoxy,
R
5Represent hydrogen, halogen, (C
1-C
4)-alkyl, single methyl fluoride, difluoromethyl, trifluoromethyl, (C
1-C
4)-alkoxyl group, single fluorine methoxyl group, difluoro-methoxy or trifluoromethoxy,
R
6Represent the group of following formula
Wherein
* be meant the tie point with this pyrazoles,
Ring U represents phenyl, pyridyl, pyrimidyl or pyrazinyl,
Wherein phenyl, pyridyl, pyrimidyl and pyrazinyl can be independently from each other halogen, (C by 1 to 3
1-C
4)-alkyl, trifluoromethyl, hydroxyl, (C
1-C
4The substituting group of)-alkoxyl group and trifluoromethoxy replaces,
Wherein at the (C of these parts
1-C
4)-alkyl and (C
1-C
4)-alkoxyl group can be independently from each other hydroxyl and (C by 1 or 2
1-C
4The substituting group of)-alkoxyl group replaces,
And
Ring V
1Representative is fused to the benzyl ring on the ring U or is fused to 5-or the 6-unit heteroaryl ring that encircles on the U,
Wherein said benzyl ring and described 5-or 6-unit heteroaryl ring can be independently from each other halogen, cyano group, (C by 1 to 4
1-C
4)-alkyl, trifluoromethyl, (C
1-C
4)-alkoxyl group, trifluoromethoxy, (C
1-C
4)-alkyl-carbonyl, amino, list-(C
1-C
4)-alkylamino and two-(C
1-C
4The substituting group of)-alkylamino replaces.
Compound of the present invention is that the solvate of the solvate of the compound of formula (I) and their salt, solvate and this salt, following various compound that formula (I) contains and their salt, solvate and this salt and formula (I) contain and hereinafter as the compound of application examples statement and the solvate of their salt, solvate and this salt, unless formula (I) contains and the compound of hereinafter statement has been the solvate of salt, solvate and this salt.
According to their structure, compound of the present invention can exist with stereoisomeric forms in any ratio (enantiomer, diastereomer).Therefore the present invention comprises enantiomer or diastereomer and their mixture separately.Can from the described mixture of enantiomer and/or diastereomer, isolate the composition of stereoisomerism unanimity in a known way.
If compound of the present invention exists with tautomeric form, then the present invention comprises all tautomeric forms.
The physiology of compound of the present invention harmless salt is preferably as in the scope of the present invention
SaltIt also comprises the salt that itself is not suitable for pharmaceutical use but can for example be used for the separation or the purification of compound of the present invention.
The harmless salt of the physiology of compound of the present invention comprises the acid salt of mineral acid, carboxylic acid and sulfonic acid, for example, hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, ethyl sulfonic acid, toluenesulphonic acids, Phenylsulfonic acid, naphthalene disulfonic acid, acetate, trifluoroacetic acid, propionic acid, lactic acid, tartrate, oxysuccinic acid, citric acid, fumaric acid, toxilic acid and benzoic salt.
The harmless salt of the physiology of compound of the present invention also comprises the salt of common alkali, for example with preferred as alkali salt (for example sodium and sylvite), alkaline earth salt (for example calcium and magnesium salts) with by ammonia or contain the organic amine of 1 to 16 carbon atom, for example and preferred ethamine, diethylamine, triethylamine, ethyl diisopropylamine, monoethanolamine, diethanolamine, trolamine, dicyclohexyl amine, dimethylaminoethanol, PROCAINE HCL, PHARMA GRADE, dibenzylamine,
N-methylmorpholine, arginine, Methionin, quadrol and
NThe ammonium salt that-methyl piperidine generates.
By with the solvent molecule coordination solid-state or liquid in form the compound of the present invention of complex compound those forms be known as within the scope of the invention
SolvateHydrate is a kind of special shape of solvate, wherein with water generation coordination.Within the scope of the invention, hydrate is preferably as solvate.
In addition, the present invention also comprises the prodrug of compound of the present invention.Term " prodrug " comprise this in activity or non-activity are biologically arranged but in vivo in the process (for example by metabolism or by hydrolysis) change into the compound of compound of the present invention.
Within the scope of the invention, unless indicate separately, substituting group has following meanings:
AlkylRepresentative within the scope of the invention contains the straight or branched alkyl residue of 1 to 4 or 1 to 3 carbon atom.For example and preferably, we can mention: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl and the tertiary butyl.
Alkyl-carbonylRepresentative within the scope of the invention contains the straight or branched alkyl residue of 1 to 4 carbon atom and 1 carbonyl that is connected in the position.For example and preferably, we can mention: methyl carbonyl, ethyl carbonyl, n-propyl carbonyl, sec.-propyl carbonyl, normal-butyl carbonyl, isobutyl-carbonyl and tertiary butyl carbonyl.
Alkoxyl groupRepresentative within the scope of the invention contains the straight or branched alkoxy residue of 1 to 4 or 1 to 3 carbon atom.For example and preferably, we can mention: methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy and tert.-butoxy.
List-alkylaminoRepresentative within the scope of the invention contains the amino of the straight or branched alkyl substituent with 1 to 4 carbon atom.For example and preferably, we can mention: methylamino, ethylamino, n-propyl amino, sec.-propyl amino, normal-butyl amino and tertiary butyl amino.
Two-alkylaminoRepresentative within the scope of the invention contains two amino that have the identical or different straight or branched alkyl substituent of 1 to 4 carbon atom separately.For example and preferably, we can mention:
N, N-dimethylamino,
N, N-diethylamino,
N-ethyl-
N-methylamino,
N-methyl-
N-n-propyl amino,
N-sec.-propyl-
N-n-propyl amino,
N, N-diisopropylaminoethyl,
N-normal-butyl-
N-methylamino and
N-the tertiary butyl-
N-methylamino.
The alkyl sulfonyl-amino carbonylRepresent within the scope of the invention to connect and have through alkylsulfonyl and be connected to the substituent amino of straight or branched alkyl sulphonyl that contains 1 to 4 carbon atom on the N-atom through carbonyl.For example and preferably, we can mention: methyl sulphonyl aminocarboxyl, ethylsulfonyl aminocarboxyl, n-propyl sulfonyl amino carbonyl, sec.-propyl sulfonyl amino carbonyl, normal-butyl sulfonyl amino carbonyl and tertiary butyl sulfonyl amino carbonyl.
HeteroarylRepresentative within the scope of the invention is fused to ring U and goes up, contains 5 or 6 annular atomses altogether and contain maximum three monocyclic aromatic heterocycles (heteroaromatic) that are selected from the identical or different ring hetero atom of N, O and/or S.For example, we can mention: furyl, pyrryl, thienyl, pyrazolyl, imidazolyl, thiazolyl,
Azoles base, different
Azoles base, isothiazolyl, triazolyl,
Di azoly, thiadiazolyl group, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl and triazinyl.Contain maximum two monocycles that are selected from the ring hetero atom of N, O and/or S
5-or 6-unit heteroarylResidue is preferred, for example furyl, thienyl, thiazolyl,
Azoles base, isothiazolyl, different
Azoles base, pyrazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl.
HalogenComprise fluorine, chlorine, bromine and iodine within the scope of the invention.Fluorine and chlorine are preferred.
At R
2, R
6Or in this group chemical formula that can represent of Q, exist the line endpoints of symbol ##, * or # not represent carbon atom or CH
2Group, but to indicated atom (R in each case
2, R
6Or amino bonded is on it) the composition of key.
If the residue in the compound of the present invention is substituted, unless indicate separately, this residue can be substituted once or more than once.Within the scope of the invention, for all residues more than once occurring, their implication is independently of one another.Preferably replaced by one, substituting group that two or three are identical or different.Especially preferably replaced by a substituting group.
The solvate of the compound of preferably following within the scope of the invention formula (I) and their salt, solvate and this salt, wherein
Q represents phenyl or pyridyl,
R
1Represent hydrogen, cyano group, (C
1-C
3)-alkyl, trifluoromethyl, (C
1-C
3)-alkoxyl group or trifluoromethoxy,
R
2Represent phenyl, naphthyl or 5-or 6-unit heteroaryl,
Wherein phenyl, naphthyl and 5-or 6-unit heteroaryl can be independently from each other halogen, cyano group, (C by 1 or 2
1-C
4)-alkyl, trifluoromethyl, (C
1-C
4The substituting group of)-alkoxyl group and trifluoromethoxy replaces,
R
3Representation hydroxy carbonyl, aminocarboxyl, cyano group aminocarboxyl, (C
1-C
4)-alkyl sulfonyl-amino carbonyl,
Bisoxazoline ketone group (oxadiazolonyl) or tetrazolium-5-base,
Wherein
Bisoxazoline ketone group (oxadiazolonyl) can be replaced by methyl substituents,
R
4Represent hydrogen, halogen, (C
1-C
4)-alkyl, difluoromethyl, trifluoromethyl, (C
1-C
4)-alkoxyl group, difluoro-methoxy or trifluoromethoxy,
R
5Represent hydrogen, halogen, (C
1-C
4)-alkyl, difluoromethyl, trifluoromethyl, (C
1-C
4)-alkoxyl group, difluoro-methoxy or trifluoromethoxy,
R
6Represent the group of following formula
Wherein
* be meant the tie point with this pyrazoles,
Ring U represents phenyl, pyridyl, pyrimidyl or pyrazinyl,
Wherein phenyl, pyridyl, pyrimidyl and pyrazinyl can be independently from each other halogen and (C by 1 to 3
1-C
4The substituting group of)-alkyl replaces,
And
Ring V
1Representative is fused to the benzyl ring on the ring U or is fused to 5-or the 6-unit heteroaryl ring that encircles on the U,
Wherein said benzyl ring and described 5-or 6-unit heteroaryl ring can be independently from each other halogen, cyano group, (C by 1 to 4
1-C
4)-alkyl, trifluoromethyl, (C
1-C
4)-alkoxyl group, (C
1-C
4)-alkyl-carbonyl, amino, list-(C
1-C
4)-alkylamino and two-(C
1-C
4The substituting group of)-alkylamino replaces.
The compound of following formula (I) and the solvate of their salt, solvate and this salt also are preferred in the scope of the present invention, wherein
Q represents phenyl,
R
1Represent hydrogen, methyl or trifluoromethyl,
R
2Represent phenyl,
Wherein phenyl can be replaced by 1 or 2 substituting group that is independently from each other fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxyl group, oxyethyl group and trifluoromethoxy,
R
3The representation hydroxy carbonyl,
R
4Represent hydrogen, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxyl group, oxyethyl group, difluoro-methoxy or trifluoromethoxy,
R
5Represent hydrogen,
R
6Represent the group of following formula
Wherein
* be meant the tie point with this pyrazoles,
A
1Represent CR
10Or N,
Wherein
R
10Represent hydrogen, fluorine, chlorine or methyl,
A
2Represent CR
11Or N,
Wherein
R
11Represent hydrogen, fluorine, chlorine or methyl,
A
3Represent CR
12Or N,
Wherein
R
12Represent hydrogen, fluorine, chlorine, methyl or methoxy,
A
4Represent CR
13Or N,
Wherein
R
13Represent hydrogen, fluorine, chlorine, methyl or methoxy,
D
1Represent CR
15Or N,
Wherein
R
15Represent hydrogen, fluorine, chlorine or methyl,
D
2Represent CR
16Or N,
Wherein
R
16Represent hydrogen, fluorine, chlorine or methyl,
D
3Represent CR
17Or N,
Wherein
R
17Represent hydrogen, fluorine, chlorine or methyl,
D
4Represent CR
18Or N,
Wherein
R
18Represent hydrogen, fluorine, chlorine or methyl,
D
5Represent NR
19, O or S,
Wherein
R
19Represent hydrogen or methyl,
Condition is group D
1, D
2, D
3, D
4And D
5In at least one represent N or NR
19,
E
1Represent CR
21Or N,
Wherein
R
21Represent hydrogen, fluorine, chlorine or methyl,
E
2Represent CR
22Or N,
Wherein
R
22Represent hydrogen, fluorine, chlorine or methyl,
E
3Represent CR
23Or N,
Wherein
R
23Represent hydrogen, fluorine, chlorine, methyl or amino,
E
4Represent CR
24Or N,
Wherein
R
24Represent hydrogen, fluorine, chlorine or methyl,
Condition is group E
2, E
3And E
4In maximum two represent N,
G
1Represent CR
26Or N,
Wherein
R
26Represent hydrogen, fluorine, chlorine or methyl,
G
2Represent CR
27Or N,
Wherein
R
27Represent hydrogen, fluorine, chlorine or methyl,
G
3Represent CR
28Or N,
Wherein
R
28Represent hydrogen, fluorine, chlorine, methyl or amino,
G
4Represent CR
29Or N,
Wherein
R
29Represent hydrogen, fluorine, chlorine or methyl,
Condition is a group G
2, G
3And G
4In maximum two represent N,
K
1Represent CR
35Or N,
Wherein
R
35Represent hydrogen, fluorine, chlorine or methyl,
L
1Represent CR
41Or N,
Wherein
R
41Represent hydrogen, fluorine, chlorine or methyl,
R
7Represent hydrogen, fluorine, chlorine, methyl, hydroxyl, methoxy or ethoxy,
R
8Represent hydrogen, fluorine, chlorine, methyl or methoxy,
R
9Represent hydrogen, fluorine, chlorine, methyl, methoxyl group, amino, methylamino or dimethylamino,
R
14Represent hydrogen, fluorine, chlorine, methyl, hydroxyl, methoxy or ethoxy,
R
20Represent hydrogen, fluorine, chlorine, methyl, hydroxyl, methoxy or ethoxy,
R
25Represent hydrogen, fluorine, chlorine, methyl, hydroxyl, methoxy or ethoxy,
R
30Represent hydrogen, fluorine, chlorine, methyl, hydroxyl, methoxy or ethoxy,
R
31Represent hydrogen, fluorine, chlorine or methyl,
R
32Represent hydrogen, fluorine, chlorine or methyl,
R
33Represent hydrogen, fluorine, chlorine, methyl or amino,
R
34Represent hydrogen, fluorine, chlorine, methyl, methoxyl group, amino, methylamino or dimethylamino,
R
36Represent hydrogen, fluorine, chlorine, methyl, hydroxyl, methoxy or ethoxy,
R
37Represent hydrogen, fluorine, chlorine or methyl,
R
38Represent hydrogen, fluorine, chlorine, methyl, methoxyl group, amino, methylamino or dimethylamino,
R
39Represent hydrogen, fluorine, chlorine, methyl or amino,
And
R
40Represent hydrogen, fluorine, chlorine or methyl.
Within the scope of the invention, the compound of following formula (I) and the solvate of their salt, solvate and this salt also are preferred, wherein
Q represents phenyl,
R
1Represent hydrogen, cyano group, methyl, ethyl or trifluoromethyl,
R
2Represent phenyl,
Wherein phenyl can be independently from each other fluorine, chlorine, (C by 1 or 2
1-C
4)-alkyl, trifluoromethyl, (C
1-C
4The substituting group of)-alkoxyl group and trifluoromethoxy replaces,
R
3Representation hydroxy carbonyl or methyl sulphonyl aminocarboxyl,
R
4Represent hydrogen, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxyl group, oxyethyl group, difluoro-methoxy or trifluoromethoxy,
R
5Represent hydrogen, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxyl group, oxyethyl group, difluoro-methoxy or trifluoromethoxy,
R
6Represent the group of following formula
Wherein
* be meant the tie point with this pyrazoles,
A
1Represent CR
10Or N,
Wherein
R
10Represent hydrogen, fluorine, chlorine or methyl,
A
2Represent CR
11Or N,
Wherein
R
11Represent hydrogen, fluorine, chlorine or methyl,
A
3Represent CR
12Or N,
Wherein
R
12Represent hydrogen, fluorine, chlorine or methyl,
A
4Represent CR
13Or N,
Wherein
R
13Represent hydrogen, fluorine, chlorine or methyl,
D
1Represent CR
15Or N,
Wherein
R
15Represent hydrogen, fluorine, chlorine or methyl,
D
2Represent CR
16Or N,
Wherein
R
16Represent hydrogen, fluorine, chlorine or methyl,
D
3Represent CR
17Or N,
Wherein
R
17Represent hydrogen, fluorine, chlorine or methyl,
D
4Represent CR
18Or N,
Wherein
R
18Represent hydrogen, fluorine, chlorine or methyl,
D
5Represent NR
19, O or S,
Wherein
R
19Represent hydrogen or methyl,
Condition is group D
1, D
2, D
3, D
4And D
5In at least one represent N or NR
19,
E
1Represent CR
21Or N,
Wherein
R
21Represent hydrogen, fluorine, chlorine or methyl,
E
2Represent CR
22Or N,
Wherein
R
22Represent hydrogen, fluorine, chlorine or methyl,
E
3Represent CR
23Or N,
Wherein
R
23Represent hydrogen, fluorine, chlorine or methyl,
E
4Represent CR
24Or N,
Wherein
R
24Represent hydrogen, fluorine, chlorine or methyl,
Condition is group E
2, E
3And E
4In maximum two represent N,
G
1Represent CR
26Or N,
Wherein
R
26Represent hydrogen, fluorine, chlorine or methyl,
G
2Represent CR
27Or N,
Wherein
R
27Represent hydrogen, fluorine, chlorine or methyl,
G
3Represent CR
28Or N,
Wherein
R
28Represent hydrogen, fluorine, chlorine or methyl,
G
4Represent CR
29Or N,
Wherein
R
29Represent hydrogen, fluorine, chlorine or methyl,
Condition is a group G
2, G
3And G
4In maximum two represent N,
R
7Represent hydrogen, fluorine, chlorine or methyl,
R
8Represent hydrogen, fluorine, chlorine or methyl,
R
9Represent hydrogen, fluorine, chlorine or methyl,
R
14Represent hydrogen, fluorine, chlorine or methyl,
R
20Represent hydrogen, fluorine, chlorine or methyl,
And
R
25Represent hydrogen, fluorine, chlorine or methyl.
Within the scope of the invention, the compound of following formula (I) and the solvate of their salt, solvate and this salt are especially preferred, wherein
Q represents the group of following formula
Wherein
# is meant the tie point amino with this,
R
3The representation hydroxy carbonyl,
R
4Represent hydrogen, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxyl group, difluoro-methoxy or trifluoromethoxy,
R
5Represent hydrogen or fluorine,
R
1Represent hydrogen or methyl,
R
2Represent phenyl,
Wherein phenyl can be replaced by 1 or 2 substituting group that is independently from each other fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxyl group, oxyethyl group or trifluoromethoxy,
R
6Represent the group of following formula
Wherein
* be meant the tie point with this pyrazoles,
A
1Represent CR
10Or N,
Wherein
R
10Represent hydrogen, fluorine, chlorine or methyl,
R
7Represent hydrogen, fluorine, chlorine or methyl,
R
11Represent hydrogen, fluorine, chlorine or methyl.
Within the scope of the invention, the compound of following formula (I) and the solvate of their salt, solvate and this salt are also especially preferred, wherein
Q represents the group of following formula
Wherein
# is meant the tie point amino with this,
R
3The representation hydroxy carbonyl,
R
4Represent hydrogen, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxyl group, difluoro-methoxy or trifluoromethoxy,
R
5Represent hydrogen,
R
1Represent methylidene,
R
2Represent the group of following formula
Wherein
The tie point of ## representative and this pyrazoles,
R
42Represent hydrogen, fluorine, chlorine, trifluoromethyl, methyl, ethyl, methoxy or ethoxy,
R
43Represent hydrogen, fluorine, chlorine or methyl,
R
6Represent the group of following formula
Wherein
* be meant the tie point with this pyrazoles,
A
1Represent CR
10Or N,
Wherein
R
10Represent hydrogen, fluorine or chlorine,
A
2Represent CR
11,
Wherein
R
11Represent hydrogen, fluorine, chlorine or methyl,
A
3Represent N,
A
4Represent N,
E
1Represent CR
21,
Wherein
R
21Represent hydrogen,
E
2Represent N,
E
3Represent CR
23,
Wherein
R
23Represent hydrogen or amino,
E
4Represent N,
G
1Represent CR
26,
Wherein
R
26Represent hydrogen,
G
2Represent N,
G
3Represent CR
28,
Wherein
R
28Represent hydrogen or amino,
G
4Represent N,
K
1Represent N,
R
7Represent hydrogen, fluorine, chlorine, methyl, methoxy or ethoxy,
R
8Represent hydrogen,
R
9Represent hydrogen,
R
20Represent hydrogen, fluorine, chlorine, methyl, methoxy or ethoxy,
R
25Represent hydrogen, fluorine, chlorine, methyl, methoxy or ethoxy,
R
30Represent hydrogen, fluorine, chlorine, methyl, methoxy or ethoxy,
R
31Represent hydrogen, fluorine or chlorine,
R
32Represent hydrogen, fluorine or chlorine,
R
33Represent hydrogen,
And
R
34Represent hydrogen.
Within the scope of the invention, R
3The compound of the formula of representation hydroxy carbonyl (I) also is preferred.
Within the scope of the invention, R
1It also is preferred representing the compound of the formula (I) of hydrogen.
Within the scope of the invention, R
1The compound of the formula of represent methylidene (I) also is preferred.
Within the scope of the invention, R
2The compound of representing the formula (I) of phenyl also is preferred, and wherein phenyl can be replaced by 1 or 2 substituting group that is independently from each other fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxyl group, oxyethyl group or trifluoromethoxy.
Within the scope of the invention, the compound of following formula (I) also is preferred, wherein
R
2Represent the group of following formula
Wherein
The tie point of ## representative and this pyrazoles,
R
42Represent fluorine, chlorine, trifluoromethyl, methyl, ethyl, methoxy or ethoxy,
R
43Represent hydrogen, fluorine, chlorine or methyl.
Within the scope of the invention, the compound of following formula (I) also is preferred, wherein
Q represents the group of following formula
Wherein
# is meant the tie point amino with this,
R
3The representation hydroxy carbonyl,
R
4Represent hydrogen, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxyl group, difluoro-methoxy or trifluoromethoxy,
R
5Represent hydrogen or fluorine.
Within the scope of the invention, the compound of following formula (I) also is preferred, wherein
R
6Represent the group of following formula
Wherein
* be meant the tie point with this pyrazoles,
A
1Represent CR
10,
Wherein
R
10Represent hydrogen, fluorine, chlorine or methyl,
A
2Represent CR
11,
Wherein
R
11Represent hydrogen, fluorine, chlorine or methyl,
A
3Represent N,
A
4Represent N,
R
7Represent hydrogen, fluorine, chlorine, methyl, methoxy or ethoxy,
R
8Represent hydrogen, fluorine, chlorine, methyl or methoxy,
R
9Represent hydrogen, fluorine, chlorine, methyl, methoxyl group, amino, methylamino or dimethylamino.
Within the scope of the invention, the compound of following formula (I) also is preferred, wherein
R
6Represent the group of following formula
Wherein
* be meant the tie point with this pyrazoles,
A
1Represent CR
10,
Wherein
R
10Represent hydrogen or fluorine,
A
2Represent CR
11,
Wherein
R
11Represent hydrogen,
A
3Represent N,
A
4Represent N,
R
7Represent hydrogen, fluorine, chlorine, methyl, methoxy or ethoxy,
R
8Represent hydrogen,
R
9Represent hydrogen.
Within the scope of the invention, the compound of following formula (I) also is preferred, wherein
R
6Represent the group of following formula
Wherein
* be meant the tie point with this pyrazoles,
E
1Represent CR
21,
Wherein
R
21Represent hydrogen or fluorine,
E
2Represent N,
E
3Represent CR
23,
Wherein
R
23Represent hydrogen or amino,
E
4Represent N,
G
1Represent CR
26,
Wherein
R
26Represent hydrogen or fluorine,
G
2Represent N,
G
3Represent CR
28,
Wherein
R
28Represent hydrogen or amino,
G
4Represent N,
R
20Represent hydrogen, fluorine, chlorine, methyl, methoxy or ethoxy,
R
25Represent hydrogen, fluorine, chlorine, methyl, methoxy or ethoxy.
Independent indicated residue definition also can arbitrarily replace to the residue definition of other combination in the combination separately of residue or preferably combination, and is irrelevant with the combination separately of described residue.
The combination of two or more above-mentioned preferable range is especially preferred.
Another object of the present invention is the manufacture method of the compound of the present invention of formula (I-1), wherein R
3The representation hydroxy carbonyl is characterized in that,
The compound of [A] formula (II)
R wherein
1And R
2Have the implication separately that above provides,
In inert solvent, transform the compound of an accepted way of doing sth (III-A) with halogenating agent
R wherein
1And R
2Has the implication separately that above provides
And
X
1Represent halogen, particularly represent bromine or iodine,
Its subsequently in inert solvent in the presence of alkali and suitable palladium catalyst with the reaction of the compound of formula (IV)
R wherein
6Has the implication that above provides
And
T
1Represent hydrogen or two residue T
1Xing Cheng – C (CH together
3)
2-C (CH
3)
2-or-CH
2C (CH
3)
2CH
2-bridge,
To form the compound of formula (V-A)
R wherein
1, R
2And R
6Have the implication separately that above provides,
And its subsequently in inert solvent in the presence of appropriate catalyst with the reaction of the compound of formula (VI-A)
Wherein Q, R
4And R
5Has the implication separately that above provides
And
T
2Representative (C
1-C
4)-alkyl,
X
2Represent halogen, preferred bromine,
To form the compound of formula (VII)
?(VII),
Wherein Q, T
2, R
1, R
2, R
4, R
5And R
6Have the implication separately that above provides,
Or
The compound of [B] formula (II) in inert solvent in the presence of appropriate catalyst with the reaction of the compound of formula (VI-A) to form the compound of formula (III-B)
Wherein Q, R
1, R
2, R
4And R
5Have the implication separately that above provides,
And
T
2Representative (C
1-C
4)-alkyl,
And it transforms the compound of an accepted way of doing sth (V-B) subsequently with halogenating agent in inert solvent
Wherein Q, T
2, X
1, R
1, R
2, R
4And R
5Have the implication separately that above provides,
And
X
1Represent halogen, preferred bromine,
And its subsequently in inert solvent in the presence of alkali and suitable palladium catalyst with the reaction of the compound of formula (IV) forming the compound of formula (VII),
Or
[C] makes the compound of formula (VIII)
R wherein
6Have the implication that above provides and
X
3Represent halogen, preferred bromine or iodine,
In inert solvent in the presence of suitable palladium catalyst with the trimethyl silyl acetonitrile reaction to form the compound of formula (IX)
?(IX),
R wherein
6Have the implication that above provides,
And its subsequently in inert solvent in the presence of suitable alkali with the reaction of the ester of formula (X)
R wherein
1Have the implication that above provides and
T
3Representative (C
1-C
4)-alkyl,
To form the compound of formula (XI)
?(XI),
R wherein
1And R
6Have the implication separately that above provides and
Ak
+Represent basic ion, preferred sodium,
And it uses the hydrazine of formula (XII) to transform subsequently
R wherein
2Have the implication that above provides,
The compound of an accepted way of doing sth (V-A), this further reacts the compound that forms formula (VII) according to aforesaid method [A],
The compound of the formula of Chan Shenging (VII) transforms the carboxylic acid of an accepted way of doing sth (I-1) subsequently by the hydrolysis of ester in each case
Wherein Q, R
1, R
2, R
4, R
5And R
6Have the implication separately that above provides,
Its optional and corresponding (i) solvent and/or (ii) alkali or acid-respons to form the solvate of its solvate, salt and/or this salt.
Elemental bromine and acetate, 1,3-two bromo-5, the 5-T10, particularly
N-bromo-succinimide (NBS),
N-iodo succinimide (NIS), the optional α that adds, α '-azo two (isopropyl cyanide) is suitable as step (II) → (III-A) or the halogenating agent (III-B) → (V-B) (AIBN) as initiator.
When using NBS or NIS, preferably in acetonitrile in 0 ℃ to+100 ℃ temperature range, use 1 with working as, 3-two bromo-5, during the 5-T10, preferably in methylene dichloride in-20 ℃ to+30 ℃ temperature range, carry out step (II) → (III-A) or the halogenation (III-B) → (V-B).
It is for example pure being used for step (III-A)+(IV) → (V-A) and inert solvent (V-B)+(IV) → (VII), as methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol or the trimethyl carbinol, ether, as diethyl ether, dioxane, tetrahydrofuran (THF), glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbon, as benzene, dimethylbenzene, toluene, hexane, hexanaphthene or petroleum fractions, or other solvent, as dimethyl formamide (DMF), methyl-sulphoxide (DMSO),
N, N'-dimethyl allene urea (DMPU),
N-methyl-2-pyrrolidone (NMP), pyridine, acetonitrile or water.Also can use the mixture of above-mentioned solvent.The mixture of dimethyl formamide and water is preferred.
Mineral alkali commonly used is suitable as and is used for step (III-A)+(IV) → (V-A) and alkali (V-B)+(IV) → (VII).These are particularly including alkali metal hydroxide, the oxyhydroxide of lithium, sodium or potassium for example, alkali metal hydrocarbonate, as the supercarbonate of sodium or potassium, basic metal or alkaline earth metal carbonate are as the carbonate of lithium, sodium, potassium, calcium or caesium, or alkali metal hydrogen phosphate, as Sodium phosphate dibasic or dipotassium.Preferred yellow soda ash or the potassium of using.
Activated carbon-carried palladium, acid chloride (II), four-(triphenyl phosphine)-palladium (0), two-(triphenyl phosphine)-Palladous chloride (II), two-(acetonitrile)-Palladous chloride (II) and [1, two (diphenylphosphino) ferrocene of 1'-] dichloro palladium (II)-methylene dichloride complex compound for example be suitable as be used for step (III-A)+(IV) → (V-A) and (V-B)+(IV) → (VII) palladium catalyst of [" Suzuki coupling "] [referring to people such as for example Hassan J.
Chem. Rev. 102, 1359-1469 (2002)].
Reaction (III-A)+(IV) → (V-A) and (V-B)+(IV) → (VII) usually at+20 ℃ to+150 ℃ is preferably carried out in+50 ℃ to+100 ℃ temperature range.
Be used for step (V-A)+(VI-A) → (VII) and (II)+(VI-A) → (III-B) inert solvent and be for example ether, as diethyl ether, dioxane, tetrahydrofuran (THF), glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbon, as benzene, dimethylbenzene, toluene, hexane, hexanaphthene or petroleum fractions, or other solvent, as dimethyl formamide, methyl-sulphoxide,
N, N'-dimethyl allene urea (DMPU),
N-methyl-2-pyrrolidone (NMP), pyridine, acetonitrile or water.Also can use the mixture of above-mentioned solvent.The preferred toluene that uses.
Following these are suitable as and are used for linked reaction (V-A)+(VI-A) → (VII) and transition-metal catalyst (II)+(VI-A) → (III-B): copper catalyst, as cupric iodide (I), and palladium catalyst, as activated carbon-carried palladium, two (dibenzylidene-acetone)-palladiums (0), three (dibenzylidene-acetone)-two palladiums (0), four (triphenyl phosphine)-palladiums (0), acid chloride (II), two (triphenyl phosphine)-Palladous chlorides (II), two (acetonitrile)-Palladous chlorides (II) or [1, two (diphenylphosphino) ferrocene of 1'-]-Palladous chloride (II), optional and additional phosphine (phosphane) part, for example (2-xenyl) two-
The tertiary butylPhosphine, dicyclohexyl [2', 4', 6'-three (1-methylethyl) biphenyl-2-yl] phosphine (XPHOS), two (2-phenyl phosphino-phenyl) ether (DPEphos) or 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl xanthene (Xantphos) associating [also referring to, for example, people such as Hassan J.
Chem. Rev. 102, 1359-1469 (2002); Farina V., Krishnamurthy V. and Scott W. J.:
The Stille Reaction,Wiley, New York, 1998].
Step (V-A)+(VI-A) → (VII) and (II)+(VI-A) → (III-B) usually at+20 ℃ to+200 ℃, preferably+80 ℃ to+180 ℃ temperature range in, choose wantonly in microwave and carry out.This reaction can be carried out under the pressure (for example 0.5 to 5 crust) of normal pressure, rising or reduction.It carries out under normal pressure usually.
Step (VIII) → (IX) is people such as Hartwig J.F.,
J. Am. Chem. Soc.2005,
127, carry out under the condition of describing among the 15824-15832.
In reaction (IX)+(X) → (XI), inert solvent is an ether for example, as diethyl ether, dioxane, tetrahydrofuran (THF), glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbon, as benzene, dimethylbenzene, toluene, hexane, hexanaphthene or petroleum fractions, or other solvent, as dimethyl formamide or acetonitrile.Also can use the mixture of above-mentioned solvent.The preferred tetrahydrofuran (THF) that uses.
Inorganic or organic bases commonly used is suitable as the alkali that is used for this reaction.These preferably include alkalimetal hydride, as sodium hydride, alkali metal hydroxide, the oxyhydroxide of lithium, sodium or potassium for example, alkali metal alcoholates is as sodium methylate or potassium methylate, sodium ethylate or potassium ethylate or potassium tert.-butoxide, amides, as sodium amide, two-(trimethyl silyl) lithium amide, two-(trimethyl silyl) sodium amide or two-(trimethyl silyl) amination potassium, or diisopropylaminoethyl lithium or organometallic compound, as butyllithium or phenyl lithium.The preferred sodium hydride that uses.
Step (IX)+(X) → (XI) is usually at-78 ℃ to+100 ℃, preferred-20 ℃ to+80 ℃ temperature range, choose wantonly in microwave and carry out.This reaction can be carried out under the pressure (for example 0.5 to 5 crust) of normal pressure, rising or reduction.It carries out under normal pressure usually.
React (XI)+(XII) → (V-A) for example people such as Sorokin V. I.,
Chem. Heterocycl. Comp.2003,39, carry out under the condition of describing among the 937-942.
By common methods, by in inert solvent with acid or this ester of alkaline purification, with the compound of the ester hydrolysis accepted way of doing sth (I-1) of compound (VII), under one situation of back, earlier by the salt that forms being changed into the free carboxy acid with acid treatment.Under the situation of the tert-butyl ester, preferably carry out the cracking of ester with acid.
Water or be used for ester cracked organic solvent commonly used and be suitable as the inert solvent that is used for these reactions.These preferably include alcohol, as methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol or the trimethyl carbinol, or ether, as diethyl ether, tetrahydrofuran (THF), dioxane or glycol dimethyl ether, or other solvent, as acetone, methylene dichloride, dimethyl formamide or methyl-sulphoxide.Also can use the mixture of above-mentioned solvent.Under the esterolytic situation of alkalescence, preferably make water and dioxane, tetrahydrofuran (THF), methyl alcohol and/or alcoholic acid mixture, under the situation of nitrile hydrolysis, be preferably water and/or n-propyl alcohol.With the situation of trifluoroacetic acid reaction under, preferably use methylene dichloride, with the situation of hcl reaction under, preferably use tetrahydrofuran (THF), diethyl ether, dioxane or water.
Mineral alkali commonly used is suitable as alkali.These preferably include basic metal or alkaline earth metal hydroxides, and for example oxyhydroxide of sodium, lithium, potassium or barium, or basic metal or alkaline earth metal carbonate are as the carbonate of sodium, potassium or calcium.Sodium hydroxide or lithium hydroxide are especially preferred.
Sulfuric acid, hydrogenchloride/hydrochloric acid, hydrogen bromide/Hydrogen bromide, phosphoric acid, acetate, trifluoroacetic acid, toluenesulphonic acids, methylsulfonic acid or the trifluoromethanesulfonic acid of optional interpolation water or its mixture are suitable as usually and are used for the acid of ester cracked.Hydrogenchloride or trifluoroacetic acid are preferred under the situation of the tert-butyl ester, and hydrochloric acid is preferred under the situation of methyl esters.
The ester cracking is usually at 0 ℃ to+100 ℃, preferred+carry out in 0 ℃ to+50 ℃ the temperature range.
Above-mentioned reaction can be carried out under the pressure (for example 0.5 to 5 crust) of normal pressure, rising or reduction.This reaction is carried out under normal pressure in each case usually.
The compound of formula (II) can be buied, and is known or can prepare similarly with known method in the document [referring to for example WO 2004/050651 18-19 page or leaf from document; People such as Sorokin V. I.,
Chem. Heterocycl. Comp.2003,39,937-942].
Formula (IV) and compound (VI-A) can be buied, and knownly from document maybe can obtain by known method.
The method of describing before can illustrating by following synthetic schemes that is used to make compound of the present invention:
Schema 1
[a) at X
1Under the situation of=bromine, AcOH or N-bromosuccinimide, acetonitrile, RT is to reflux temperature; At X
1Under the situation of=I: N-iodosuccinimide, acetonitrile, RT is to reflux temperature; B) Pd (PPh
3)
4, Na
2CO
3(aq), DMF, 110 ℃; C) Pd (OAc)
2, K
3PO
4, (2-xenyl) two-tertiary butyl phosphine, toluene, reflux temperature; D) NaOH (aq), dioxane/water, RT is to reflux temperature].
Schema 2
[a): Pd (OAc)
2, K
3PO
4, (2-xenyl) two-tertiary butyl phosphine, toluene, reflux temperature; B): at X
1Under the situation of=bromine, AcOH or N-bromosuccinimide, acetonitrile, RT is to reflux temperature; At X
1Under the situation of=I: N-iodosuccinimide, acetonitrile, RT is to reflux temperature; C) Pd (PPh
3)
4, Na
2CO
3(aq), DMF, 110 ℃; D) NaOH (aq), dioxane/water, RT is to reflux temperature].
Schema 3
[a) three (dibenzylidene-acetone), two palladiums, Xantphos, zinc fluoride, DMF, 90 ℃ are [at X
3Under the situation of=Br, I, referring to: Lingyun Wu, John F. Hartwig,
J. Am. Chem. Soc.(2005),
127, 15824-15832.]; B) sodium hydride, THF, adds corresponding ester subsequently by 0 ℃-RT; RT-〉60 ℃; C) 1N hydrochloric acid, reflux temperature].
R
3Represent aminocarboxyl, cyano group aminocarboxyl or (C
1-C
4Other compound of the present invention of the formula (I) of)-alkyl sulfonyl-amino carbonyl can react by method known to those skilled in the art by the carboxylic acid according to the present invention that makes formula (I-1) and prepare, referring to for example Kwon C.-H.,
Synth. Commun.1987,17,1677-1682; McDonald I. M.,
J. Med. Chem.2007,50,3101-3112.
R
3Represent 1,3,4-
The compound of the present invention of the formula (I) of diazole-2 (3H) ketone-5-base can be prepared as follows: the compound that at first with hydrazine the compound of formula (VII) is transformed an accepted way of doing sth (XIII) in inert solvent
Wherein Q, R
1, R
2, R
4, R
5And R
6Have the implication that above provides,
Subsequently in inert solvent with phosgene or phosgene counterpart, for example
N, N'The reaction of-carbonyl dimidazoles.
Especially, alcohol, as methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol or the trimethyl carbinol, or ether, be suitable as the inert solvent of the first step that is used for this reaction sequence as diethyl ether, dioxane, tetrahydrofuran (THF), glycol dimethyl ether or diethylene glycol dimethyl ether.Also can use the mixture of these solvents.The preferred mixture that uses methyl alcohol and tetrahydrofuran (THF).Preferably in ether, particularly in tetrahydrofuran (THF), carry out second reactions steps.This reaction is carried out in 0 ℃ to+70 ℃ temperature range under normal pressure usually.
R
3Represent 1,2,4-
The compound of the present invention of the formula (I) of diazole-5 (2H) ketone-3-base can be by known method in document with the compound of formula (VI-B)
Wherein Q, X
2, R
4And R
5Have the implication separately that above provides,
Transform the compound of an accepted way of doing sth (XIV)
Wherein Q, X
2, R
4And R
5Have the implication separately that above provides,
Provide suitable protecting group PG for it subsequently
1, and the compound of gained formula (XV)
Wherein Q, X
2, R
4And R
5Has the implication separately that above provides
And
PG
1Represent protecting group,
Further react the compound that forms formula (XV) according to aforesaid method [A] or [B]
?(XV),
Wherein Q, R
1, R
2, R
4, R
5, R
6And PG
1Have the implication separately that above provides,
Subsequently by this protecting group of standard method cracking, and the compound of gained formula (I-2)
Wherein Q, R
1, R
2, R
4, R
5And R
6Have the implication separately that above provides,
Optional and corresponding (i) solvent and/or (ii) alkali or acid-respons to form the solvate of its solvate, salt and/or this salt.
The reaction (VI-B) → (XIV) by method known to those skilled in the art carry out [referring to for example Iwao M., Kurashi T.,
J. Heterocycl. Chem.1979,16,689-698].
For example allyl group, trityl, 2-nitrobenzyl, 2-trimethylsilylethoxymethyl (SEM), 2-cyano ethyl, methoxy-benzyl, dimethoxy-benzyl and trimethoxy benzyl are suitable as the protecting group PG in the reaction (XIV) → (XV)
1[referring to people such as for example Weller H.N.,
Heterocycles1993,36,1027-1038].The protecting group cracking of reaction in (XV) → (I-2) by method known to those skilled in the art carry out [referring to Green T. W., Wuts P.G.M.,
Protective Groups in Organic Synthesis,The 3rd edition, John Wiley and Sons, 1999].
R
3Represent the compound of the present invention of the formula (I) of tetrazolium-5-base to be prepared as follows: known method transforms the compound of formula (VI-B) compound of an accepted way of doing sth (XVI) in document
Wherein Q, X
2, R
4And R
5Have the implication separately that above provides,
Provide suitable protecting group PG for it subsequently
2, and gained formula (XVII-A) or compound (XVII-B)
Wherein Q, X
2, R
4And R
5Has the implication separately that above provides
And
PG
2Represent protecting group
Further react according to aforesaid method [A] or [B] to form formula (XVIII-A) or compound (XVIII-B)
Wherein Q, R
1, R
2, R
4, R
5, R
6And PG
2Have the implication separately that above provides,
Subsequently by this protecting group of standard method cracking, and the compound of gained formula (I-3)
Wherein Q, R
1, R
2, R
4, R
5And R
6Have the implication separately that above provides,
Optional and corresponding (i) solvent and/or (ii) alkali or acid-respons to form the solvate of its solvate, salt and/or this salt.
The reaction (VI-B) → (XVI) by method known to those skilled in the art carry out [referring to for example Kivrakidou O., Br se S., H ü lshorst F., Griebenow N.,
Org. Lett.2004,6,1143; Wittenberger S. J., Donner B. G.,
J. Org. Chem.1993,58,4139].
For example allyl group, trityl, 2-nitrobenzyl, 2-trimethylsilylethoxymethyl (SEM), 2-cyano ethyl, methoxy-benzyl, dimethoxy-benzyl and trimethoxy benzyl are suitable as reaction (XVI) → (XVII-A) or the protecting group PG (XVII-B)
2[referring to for example Kerdesky F.A.J.,
Synth. Commun.1996,26,1007-1013].The reaction (XVIII-A) or (XVIII-B) → (I-3) in the protecting group cracking by method known to those skilled in the art carry out [referring to Green T. W., Wuts P.G.M.,
Protective Groups in Organic Synthesis,The third edition, John Wiley and Sons, 1999].
The compound of formula (VI-B) can be buied, and knownly from document maybe can obtain by known method.
Compound of the present invention has valuable pharmacological character and can be used for preventing and/or treating the various diseases and the pathology of humans and animals.
Compound of the present invention is strong selective adenosine A1 receptor antagonist, its external and interior adenosine activity that suppresses of body.
" with the selective ligands of adenosine A 1 receptor " be meant within the scope of the invention can be observed on the one hand to the A1 Adenosine Receptors tailor-made really with and do not observe the effect of A2a, A2b and A3 Adenosine Receptors hypotype on the other hand or can be observed those adenosine receptor ligands of definite more weak effect (10 times or more times), about acting on optionally test method, with reference to the test of describing among the chapters and sections B-1.
Compound of the present invention is specially adapted to prevent and/or treat cardiovascular diseases.In this respect, for example and preferably, can mention following: acute and chronic heart failure as the target indication, acute decompensated heart failure, Arterial Hypertention, coronary heart disease, stablize and unstable angina, myocardial ischemia, myocardial infarction, shock, arteriosclerosis, room and ventricular arrhythmia, transient ischemic attack, apoplexy, the inflammatory cardiovascular diseases, peripheral vessel and cardiovascular diseases, the perfusion that surrounding blood vessel is impaired, pulmonary hypertension, the spasm of coronary artery and peripheral arterial, thrombosis, thromboembolic disease, the generation of oedema, as pulmonary edema, cerebral edema, renal edema or owing to the oedema of heart failure, and restenosis, as in thrombolytic therapy, percutaneous transluminal angio plasty (PTA), coronary angioplasty between the chamber (PTCA), behind heart transplantation and the bypass surgery.
On meaning of the present invention, the term heart failure also comprises more specifically or more relevant symptom, as right heart failure, left heart failure, whole heart failure, ischemic cardiomyopathy, congestive cardiomyopathy, congenital heart disease, the lobe defective, follow the heart failure of lobe defective, mitral valve is narrow, mitral incompetence, aortic stenosis, aortic incompetence, tricuspid stenosis, tricuspid incompetence, pulmonic stenosis, pulmonary insufficiency, merge the lobe defective, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, the diabetes heart failure, alcoholic cardiomyopathy, heart storage disease, diastolic heart failure and systolic heart failure.
In addition, compound of the present invention is suitable as treatment oedema and electrolyte disturbance, particularly hypervolemia and the diuretic(s) that waits capacity (euvolemic) hyponatremia to use.
Compound of the present invention also is applicable to and prevents and/or treats multicystic kidney disease (PCKD) and syndrome of inappropriate ADH secretion (SIADH).
In addition, compound of the present invention is applicable to and treats and/or prevents ephrosis, particularly renal insufficiency and acute and chronic renal failure.On meaning of the present invention, the term renal insufficiency comprises the acute and chronic form of renal insufficiency, and the basis or relevant ephrosis, as the renal perfusion deficiency, ypotension, obstructive uropathy, glomerulonephritis, acute glomerulonephritis, matter disease between uriniferous tubules, ephrosis, as primary and congenital ephrosis, ephritis, the ephrosis that toxic substance brings out, radiographic contrast nephropathy, diabetic nephropathy, pyelonephritis, renal cyst and nephrosclerosis, its feature in diagnosis for example are unusual creatinine that reduces and/or water drainage, the unusual urea that raises, nitrogen, the blood concentration of potassium and/or creatinine, kidney enzyme (for example glutamylsynthetase) activity change, the osmotic pressure of urine or the urine amount that change, the microalbuminuria that increases, a large amount of albuminurias, damage on glomeruli and the arteriole, enlargement of pipe, hyperphosphatemia and/or need the dialysis.The present invention comprises that also compound of the present invention is used for the treatment of and/or prevents the renal insufficiency sequela, and for example pulmonary edema, heart failure, uremia, anemia, electrolyte disturbance (for example potassemia, hyponatremia) and bone are disorderly and the purposes of carbohydrate metabolism.
In addition, compound of the present invention can be used for preventing and/or treating liver cirrhosis, ascites, diabetes and diabetes sequela, for example neuropathy.
In addition, compound of the present invention is applicable to and prevents and/or treats central nervous system disorder, as anxiety state and depression, glaucoma and cancer, particularly lung cancer.
In addition, compound of the present invention can be used for preventing and/or treating inflammation, asthma, chronic obstructive pulmonary disease (COPD), pain symptom, prostatomegaly, incontinence, urocystitis, overactive bladder, suprarenalopathy, as pheochromocytoma and adrenal apoplexy, enteropathy, for example Crohn disease and diarrhoea, or menoxenia, for example dysmenorrhoea.
A further object of the present invention is that compound of the present invention is used for the treatment of and/or preventing disease, particularly the purposes of above-mentioned disease.
The invention still further relates to be used for acute mistake compensatory and chronic heart failure, hypervolemia and etc. the compound of the present invention of the method that treats and/or prevents of capacity (euvolemic) hyponatremia, liver cirrhosis, ascites, oedema, ephrosis, acute and chronic renal failure, renal insufficiency and syndrome of inappropriate ADH secretion (SIADH).
The invention still further relates to compound of the present invention is used for making and treats and/or prevents disease, the purposes of the medicine that particularly above-mentioned disease is used.
The invention still further relates to the method for compounds for treating at least a of the present invention and/or the preventing disease, particularly above-mentioned disease of using significant quantity.
Compound of the present invention can use alone or if necessary, with other active compound combined use.The invention still further relates to the medicine that contains at least a compound of the present invention and one or more additional activity materials, especially for treating and/or preventing above-mentioned disease.For example and preferably, can mention following conduct and be applicable to this associating active substance:
● organic nitrate and NO donor, for example Sodium Nitroprusside, nitroglycerine, isosorbide mononitrate, sorbide nitrate, molsidomine or SIN-1 and imbedibility NO;
● diuretic(s), particularly medullary loop hydragog(ue) and thiadiazide and thiazide diuretic;
● have the compound of positive inotropic action, for example cardiac glycoside (digoxin), beta-adrenergic and dopaminergic agonist are as isoproterenol, suprarenin, norepinephrine, Dopamine HCL and dobutamine;
● suppress the compound of cyclic guanosine monophosphate (cGMP) and/or cyclic monophosphate (cAMP) degraded, for example phosphodiesterase (PDE) 1,2,3,4 and/or 5 inhibitor, PDE 5 inhibitor particularly, as Virga, Vardenafil and Tadalafei, with PDE 3 inhibitor, as amrinone and milrinone;
● natriuretic peptide, for example " atrial natriuretic peptide " (ANP, Wy 47663), " B-type natriuretic peptide " or " brain natriuretic peptide " (BNP, Nesiritide), " C-type natriuretic peptide " are (CNP) and urodilatin;
● calcium sensitizer, for example and be preferably Simdax;
● the NO-of guanylate cyclase and protoheme-independence activator, the compound of describing among special for example WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and the WO 02/070510;
● the NO-independence of guanylate cyclase but the agent of protoheme dependent stimulation, the compound of describing among special for example WO 00/06568, WO 00/06569, WO 02/42301 and the WO 03/095451;
● the antagonist of Hou Yejiayasu acceptor, for example conivaptan, tolvaptan, RWJ-676070 or RWJ-351647;
● the inhibitor of human neutrophil elastin (HNE), for example sivelestat or DX-890 (Reltran);
● the signal transduction cascade suppresses compound, for example tyrosine kinase inhibitor, particularly Xarelto, imatinib, Gefitinib and erlotinib;
● act on the compound of energy metabolism, for example and preferably, rely on not department, perhexiline, dichloroacetate, ranolazine or trimetazidine;
● have the medicament of anti-thrombosis function, for example and preferably, be selected from anticoagulant, anti-coagulant or profibrinolytic material;
● the active substance that brings high blood pressure down, for example and preferably, be selected from inhibitor, endothelin antagonist, renin inhibitor, alpha-blocking agent, beta-blocker, mineralocorticoid receptor antagonists and the ρ-kinase inhibitor of calcium antagonist, Angiotensin AII antagonist, ACE inhibitor, vasoactive peptidase inhibitors, neutral endopeptidase; And/or
● change lipometabolic active substance, for example and preferably, be selected from thryoid receptor agonist, cholesterol synthesis inhibitor, for example and preferably, HMG-CoA-reductase enzyme or squalene synthetic inhibitor, ACAT inhibitor, CETP inhibitor, MTP inhibitor, PPAR-α-, PPAR-γ-and/or PPAR-delta agonists, cholesterol absorption inhibitor, lipase inhibitor, polymerization bile acide absorption agent, bile acide reuptake inhibithors and lipoprotein (a) antagonist;
● Na
+/ K
+The inhibitor of ATPase, for example istaroxime;
● the activator of myosin chain, for example CK-1827452;
● the agonist of LGR7 acceptor, for example Relaxin;
● the agonist of CFR-R2 acceptor, for example urocortin;
● people's chymotrypsin inhibitor, for example TPC-806.
In a preferred embodiment of the invention, compound of the present invention and diuretic(s), for example and preferably, furosemide, bumetanide, torasemide, Hydrex, chlorothiazide, hydrochlorothiazide, Hydroflumethiazide, Methyclothiazide, polythiazide, trichlormethiazide, chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide, daranide, Neptazaneat, glycerine, Isosorbide, N.F,USP MANNITOL, guanamprazine or triamterene Combined Preparation.
" medicament with anti-thrombosis function " preferably is understood that it is the compound that is selected from anticoagulant, anti-coagulant or profibrinolytic material.
In a preferred embodiment of the invention, compound of the present invention and anticoagulant, for example and preferably, acetylsalicylic acid, clopidogrel, ticlopidine or Dipyridamole Combined Preparation.
In a preferred embodiment of the invention, compound of the present invention and thrombin inhibitors, for example and preferably, ximelagatran, Melagatran, Bivalirudin or clexane Combined Preparation.
In a preferred embodiment of the invention, compound of the present invention and GPIIb/IIIa antagonist, for example and preferably, Tirofiban or ReoPro Combined Preparation.
In a preferred embodiment of the invention, compound of the present invention and factor Xa inhibitor, for example and preferably, profit cut down husky class (BAY 59-7939), DU-176b, apixaban, Ao Mishaban, fidexaban, Razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428 Combined Preparation.
In a preferred embodiment of the invention, compound of the present invention and heparin or lower molecular weight (LMW) heparin derivatives Combined Preparation.
In a preferred embodiment of the invention, compound of the present invention and vitamin K antagonist, for example and preferably, the tonka bean camphor Combined Preparation.
" medicament that brings high blood pressure down " preferably is understood that it is the compound that is selected from inhibitor, endothelin antagonist, renin inhibitor, alpha-blocking agent, beta-blocker, mineralocorticoid receptor antagonists, ρ-kinase inhibitor, prostanoid IP receptor stimulant and the diuretic(s) of calcium antagonist, Angiotensin AII antagonist, ACE inhibitor, vasoactive peptidase inhibitors, neutral endopeptidase.
In a preferred embodiment of the invention, compound of the present invention and calcium antagonist, for example and preferably, nifedipine, amlodipine, verapamil or Odizem Combined Preparation.
In a preferred embodiment of the invention, compound of the present invention and Angiotensin AII antagonist, for example and preferably, losartan, Candesartan, valsartan, telmisartan or Embusartan Combined Preparation.
In a preferred embodiment of the invention, compound of the present invention and ACE inhibitor, for example and preferably, enalapril, captopril, lisinopril, Ramipril, delapril, fosinopril, quino Puli, perindopril or Trolapril Combined Preparation.
In a preferred embodiment of the invention, compound of the present invention and vasoactive peptidase inhibitors or neutral endopeptidase (NEP) inhibitor, for example and preferably, omapatrilat or AVE-7688 Combined Preparation.
In a preferred embodiment of the invention, compound of the present invention and endothelin antagonist, for example and preferably, bosentan, darusentan, peace are doubly given birth to smooth or sitaxentan Combined Preparation.
In a preferred embodiment of the invention, compound of the present invention and renin inhibitor, for example and preferably, aliskiren, SPP-600 or SPP-800 Combined Preparation.
In a preferred embodiment of the invention, compound of the present invention and α-1-receptor-blocking agent, for example and preferably, the Prazosin Combined Preparation.
In a preferred embodiment of the invention, compound of the present invention and beta-blocker, for example and preferably, Proprasylyte, atenolol USP 23, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, Trate, carvedilol, Adaprolol, blue for Luo Er, nebivolol, epanolol or bucindolol Combined Preparation.
In a preferred embodiment of the invention, compound of the present invention and mineralocorticoid receptor antagonists, for example and preferably, antisterone, eplerenone, canrenone or print sharp sour potassium Combined Preparation.
In a preferred embodiment of the invention, compound of the present invention and ρ-kinase inhibitor, for example and preferably, fasudil, Y-27632, SAR407899, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049 Combined Preparation.
In a preferred embodiment of the invention, compound of the present invention and prostanoid IP receptor stimulant, for example and preferably, Iloprost, treprostinil, Beraprost or NS-304 Combined Preparation.
" change lipometabolic medicament " and preferably be understood that it is to be selected from CETP inhibitor, thryoid receptor agonist, cholesterol synthesis inhibitor, as HMG-CoA-reductase enzyme or squalene synthetic inhibitor, ACAT inhibitor, MTP inhibitor, PPAR-α-, PPAR-γ-and/or the compound of PPAR-delta agonists, cholesterol absorption inhibitor, polymerization bile acide absorption agent, bile acide reuptake inhibithors, lipase inhibitor and lipoprotein (a) antagonist.
In a preferred embodiment of the invention, compound of the present invention and CETP inhibitor, for example and preferably, torcetrapib (CP-529 414), JJT-705, BAY 60-5521, BAY 78-7499 or CETP-vaccine (Avant) Combined Preparation.
In a preferred embodiment of the invention, compound of the present invention and thryoid receptor agonist, for example and preferably, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214) Combined Preparation.
In a preferred embodiment of the invention, compound of the present invention with from the HMG-CoA-reductase inhibitor of Statins, for example and preferably, lovastatin, Simvastatin, Pravastatin, fluvastatin, atorvastatin, Rosuvastatin, Cerivastatin or pitavastatin Combined Preparation.
In a preferred embodiment of the invention, compound of the present invention and squalene synthetic inhibitor, for example and preferably, BMS-188494 or TAK-475 Combined Preparation.
In a preferred embodiment of the invention, compound of the present invention and ACAT inhibitor, for example and preferably, avasimibe, melinamide, pactimibe, eflucimibe or SMP-797 Combined Preparation.
In a preferred embodiment of the invention, compound of the present invention and MTP inhibitor, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130 Combined Preparation.
In a preferred embodiment of the invention, compound of the present invention and PPAR-gamma agonist, for example and preferably, pioglitazone or rosiglitazone Combined Preparation.
In a preferred embodiment of the invention, compound of the present invention and PPAR-delta agonists, for example and preferably, GW-501516 or BAY 68-5042 Combined Preparation.
In a preferred embodiment of the invention, compound of the present invention and cholesterol absorption inhibitor, for example and preferably, ezetimibe, tiqueside or Pamaqueside Combined Preparation.
In a preferred embodiment of the invention, compound of the present invention and lipase inhibitor, for example and preferably, the orlistat Combined Preparation.
In a preferred embodiment of the invention, compound of the present invention and polymerization bile acide absorption agent, for example and preferably, QUESTRAN, colestipol, colesolvam, CholestaGel or colestimide Combined Preparation.
In a preferred embodiment of the invention, compound of the present invention and bile acide reuptake inhibithors, for example and preferably, ASBT (=IBAT) inhibitor, for example AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635 Combined Preparation.
In a preferred embodiment of the invention, compound of the present invention and lipoprotein (a) antagonist, for example and preferably, Gemcabene calcium (CI-1027) or nicotinic acid Combined Preparation.
The invention still further relates to and contain at least a compound of the present invention,, and be used for the application of such use usually together with the medicine of one or more inertia, nontoxic, pharmaceutically acceptable vehicle.
But compound whole body of the present invention and/or part play a role.For this reason, they can apply by suitable pathways, for example oral, enteron aisle is outer, lung, nose, hypogloeeis, tongue, oral cavity, rectum, skin, transdermal, conjunctiva, through ear or as implant or support.
For these route of administration, compound of the present invention can be with suitable formulation administration.
According to the work of prior art situation and provide compound of the present invention fast or the formulation of the compound of the present invention that contains crystallization and/or amorphous and/or solubilized form that discharges of regulation and control be applicable to oral administration, tablet (not dressing or coated tablet for example, for example have enteric coating or slowly the dissolving or soluble dressing, it controls the release of compound of the present invention), quickly disintegrated tablet or film/disk in the oral cavity, film/lyophilized products, capsule (for example hard or soft gelatin capsule), sugar coated tablet, granule, pill, pulvis, emulsion, suspension, aerosol or solution.
The enteron aisle external administration can be avoided absorption step to carry out (for example in the intravenously, intra-arterial, heart, in the backbone or in the waist) or carry out (for example intramuscular, subcutaneous, intracutaneous, through skin or intraperitoneal) comprising under the situation of absorption.The injection of solution, suspension, emulsion, lyophilized products or sterilized powder form and infusion preparation especially are suitable as enteron aisle external administration formulation.
Inhalant dosage form (especially powder inhalator, atomizer), nasal drop, solution or sprays, the tablet that is used for tongue, hypogloeeis or orally administering, film/disk or capsule, suppository, ear or ophthalmic preparation, vaginal capsule, aqeous suspension (lotion, oscillation mixture), lipophilic suspension, ointment, creme, transdermal therapeutic system (for example patch), emulsion, paste, foam, face powder, implant or support for example are applicable to other route of administration.
Oral or enteron aisle external administration, particularly oral and intravenous administration is preferred.
Compound of the present invention can change into the formulation of regulation.This can be in a manner known way by carrying out with inertia, nontoxic, pharmaceutically acceptable mixed with excipients.These vehicle especially comprise carrier (for example Microcrystalline Cellulose, lactose, N.F,USP MANNITOL), solvent (for example liquid macrogol), emulsifying agent and dispersion agent or wetting agent (for example sodium lauryl sulphate, polyoxy sorbitol anhydride oleate), tackiness agent (for example Polyvinylpyrolidone (PVP)), synthetic and natural polymer (for example albumin), stablizer (antioxidant for example, xitix for example), tinting material (for example mineral dye, for example ferric oxide) and taste and/or smell corrigent.
Usually advantageously verified, in the enteron aisle external administration, give about 0.001 to 10 mg/kg, the amount of preferably approximately 0.01 to 1 mg/kg body weight is to realize effective result.In oral administration, this dosage is about 0.01 to 100 mg/kg, preferably approximately 0.01 to 20 mg/kg, especially preferred 0.1 to 10 mg/kg body weight.
Yet,, may must depart from the amount of regulation according to body weight, route of administration, individual response, preparation type and administration time point or the timed interval to actives.Therefore, in some cases, it may be enough that use is less than above-mentioned minimum quantity, and in other cases, must surpass set upper limit.If give bigger amount, may preferably these be divided into several single agent in one day.
Following Application Example is explained the present invention.The invention is not restricted to these embodiment.
Unless indicate separately, the per-cent among following test and the embodiment is weight percentage; Umber is a weight part.The concentration of solvent ratios, thinning ratio and liquid/liquid solution is all the time based on volume.
A. embodiment
Abbreviation and acronym:
The Ac ethanoyl
AcOH acetate
Aq. moisture
The TLC tlc
DCI direct chemical ionization (in MS)
The DMF dimethyl formamide
The DMSO methyl-sulphoxide
(with respect to the yield) of of theor. theoretical value
Eq. equivalent
ESI electron spray ionisation (in MS)
H hour
The Hal halogen
Efficient (high pressure) liquid phase chromatography of HPLC
The coupling of LC-MS C/MS (liquid chromatography-mass spectrography)
Min minute
MPLC medium pressure liquid chromatography method
The MS mass spectroscopy
The mc multiplet, (in NMR) placed in the middle
The NMR nuclear magnetic resonance spectroscopy(NMR spectroscopy)
Pd (PPh
3)
4Four (triphenyl phosphine) palladium (0)
RP anti-phase (in HPLC)
The RT room temperature
R
tThe residence time (in HPLC)
The sbr singlet, wide (in NMR)
The THF tetrahydrofuran (THF)
The UV ultraviolet spectrometry
V/v volume-volume ratio (mixture)
LC-MS, GC-MS and HPLC method:
Method 1(LC-MS):
Device type MS:Micromass ZQ; Device type HPLC:HP 1100 Series; UV DAD; Post: Phenomenex Gemini 3 μ 30 mm x 3.00 mm; Eluent A:1 premium on currency+0.5 milliliter of 50% formic acid, eluent B:1 rise acetonitrile+0.5 milliliter 50% formic acid; Gradient: 0.0 min, 90% A → 2.5 min, 30% A → 3.0 min, 5% A → 4.5 min, 5% A; Flow velocity: 0.0 min, 1 ml/min → 2.5 min/3.0 min/4.5 min, 2 ml/min; Stove: 50 ℃; UV detects: 210 nm.
Method 2(LC-MS):
Instrument: Micromass Quattro Micro MS has HPLC Agilent Series 1100; Post: Thermo Hypersil GOLD 3 μ 20 x 4 mm; Eluent A:1 premium on currency+0.5 milliliter of 50% formic acid, eluent B:1 rise acetonitrile+0.5 milliliter 50% formic acid; Gradient: 0.0 min, 100% A → 3.0 min, 10% A → 4.0 min, 10% A → 4.01 min, 100% A (flow 2.5 ml) → 5.00 min, 100% A stove: 50 ℃; Flow velocity: 2 ml/min; UV detects: 210 nm
Method 3(LC-MS):
Device type MS:Micromass ZQ; Device type HPLC:Waters Alliance 2795; Post: Phenomenex Synergi 2.5 μ MAX-RP 100A Mercury 20 mm x 4 mm; Eluent A:1 premium on currency+0.5 milliliter of 50% formic acid, eluent B:1 rise acetonitrile+0.5 milliliter 50% formic acid; Gradient: 0.0 min, 90% A → 0.1 min, 90% A → 3.0 min, 5% A → 4.0 min, 5% A → 4.01 min, 90% A; Flow velocity: 2 ml/min; Stove: 50 ℃; UV detects: 210 nm.
Method 4(LC-MS):
Instrument: Micromass QuattroPremier has Waters UPLC Acquity; Post: Thermo Hypersil GOLD 1.9 μ 50 x 1 mm; Eluent A:1 premium on currency+0.5 milliliter of 50% formic acid, eluent B:1 rise acetonitrile+0.5 milliliter 50% formic acid; Gradient: 0.0 min, 90% A → 0.1 min, 90% A → 1.5 min, 10% A → 2.2 min, 10% A stove: 50 ℃; Flow velocity: 0.33 ml/min; UV detects: 210 nm.
Method 5(LC-MS):
Instrument: Micromass Platform LCZ has HPLC Agilent Series 1100; Post: Thermo Hypersil GOLD 3 μ 20 x 4 mm; Eluent A:1 premium on currency+0.5 milliliter of 50% formic acid, eluent B:1 rise acetonitrile+0.5 milliliter 50% formic acid; Gradient: 0.0 min, 100% A → 0.2 min, 100% A → 2.9 min, 30% A → 3.1 min, 10% A → 5.5 min, 10% A; Stove: 50 ℃; Flow velocity: 0.8 ml/min; UV detects: 210 nm.
Method 6(GC-MS):
Instrument: Micromass GCT, GC6890; Post: Restek RTX-35,15 m x, 200 μ m x, 0.33 μ m; Constant flow rate by helium: 0.88 ml/min; Stove: 70 ℃; Inlet: 250 ℃; Gradient: 70 ℃, 30 ℃/min → 310 ℃ (keeping 3 minutes).
Method 7(prepares HPLC):
Instrument: Abimed Gilson Pump 305/306, Manometric Module 806; Post: Grom-Sil 120 ODS-4HE 10 μ m, 250 mm x, 40 mm; Eluent: A=water, B=acetonitrile; Gradient: 0.0 min, 10% B → 5 min, 10% B → 27 min, 98% B → 35 min, 98% B → 35.01 min, 10% B → 38 min, 10% B; Flow velocity: 50 ml/min; Column temperature: RT; UV detects: 210 nm.
Method 8(prepares HPLC):
Instrument: Abimed Gilson Pump 305/306, Manometric Module 806; Post: Grom-Sil 120 ODS-4HE 10 μ m, 250 mm x, 40 mm; Eluent: A=water+0.075% formic acid, B=acetonitrile; Gradient: 0.0 min, 10% B → 5 min, 10% B → 27 min, 98% B → 35 min, 98% B → 35.01 min, 10% B → 38 min, 10% B; Flow velocity: 50 ml/min; Column temperature: RT; UV detects: 210 nm.
Method 9(LC-MS):
Device type MS:Waters ZQ; Device type HPLC:Agilent 1100 Series; UV DAD; Post: Thermo Hypersil GOLD 3 μ 20 mm x 4 mm; Eluent A:1 premium on currency+0.5 milliliter of 50% formic acid, eluent B:1 rise acetonitrile+0.5 milliliter 50% formic acid; Gradient: 0.0 min 100%A → 3.0 min 10%A → 4.0 min 10%A → 4.1 min, 100% flow velocity: 2.5 ml/min, stove: 55 ℃; Flow velocity 2 ml/min; UV detects: 210 nm.
Method 10(LC-MS):
Instrument: Waters ACQUITY SQD UPLC System; Post: Waters Acquity UPLC HSS T3 1.8 μ 50 x 1 mm; Eluent A:1 premium on currency+0.25 milliliter of 99% formic acid, eluent B:1 rise acetonitrile+0.25 milliliter 99% formic acid; Gradient: 0.0 min, 90% A → 1.2 min, 5% A → 2.0 min, 5% A; Stove: 50 ℃; Flow velocity: 0.40 ml/min; UV detects: 210 –, 400 nm.
Starting compound and intermediate:
Embodiment 1A
4-(quinoxalin-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine
With 1.00 gram (3.75 mmole) 4-bromo-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine [Michaelis, Kappert,
Justus Liebigs Ann. Chem.1913,397,157] and 1.58 gram (7.51 mmole) quinoxalin-6-yl borate hydrochlorates be dissolved among 15 milliliters of DMF.After adding 4 milliliters of (8.00 mmole) 2M aqueous sodium carbonates, it is used argon-degassed.Add 261 milligrams of (3.75 mmoles) four (triphenyl phosphine) palladiums (0) and keep 110 ℃ temperature 4 hours.Recording by TLC after reaction finishes, adds 100 milliliters of ethyl acetate and remove solid residue by filtration on diatomite.Gained solution washs with 100 ml waters with 100 milliliters of saturated sodium-chloride water solutions.Organic phase is removed through dried over sodium sulfate and in rotatory evaporator and is desolvated.Crude product is by MPLC purification (Puriflash Analogix:40M: isohexane/ethyl acetate=1/1).This produces the target compound of 344 milligrams (theoretical values 29%).
LC-MS (method 1): R
t=1.69 min; MS (EIpos): m/z=316 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.10?(s,?3H),?2.29?(s,?3H),?5.20?(s,?2H),?7.30-7.39?(m,?2H),?7.40-7.44?(m,?2H),?7.97?(dd,?1H),?8.00?(d,?1H),?8.09?(d,?1H).?8.86?(d,?1H),?8.91?(d,?1H)。
Embodiment 2A
Methyl-2-{[4-(quinoxalin-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-5-fluorobenzene carboxylicesters
With 84.0 milligrams of (0.266 mmole) embodiment 1A, 74.4 milligrams of (0.320 mmole) methyl-2-bromo-5-fluorobenzoic acid esters [Gerard waits the people,
Tetrahedron Lett.2007,48,4123] and 79.2 milligrams of (0.373 mmole) potassiumphosphates be dissolved in 2.1 milliliters of pure toluenes.Gained solution argon-degassed.Add subsequently 5.4 milligrams of (0.024 mmole) acid chlorides (II) and 10.7 milligrams of (0.036 mmole) (2-xenyls) two-
The tertiary butylPhosphine.It was stirred 72 hours under reflux temperature.Recording by TLC after reaction finishes, adds 50 milliliters of ethyl acetate and remove solid residue by filtration on diatomite.Gained solution washs with 50 ml waters with 50 milliliters of saturated sodium-chloride water solutions subsequently with the neutralization of 1N hydrochloric acid.Organic phase is removed through dried over sodium sulfate and in rotatory evaporator and is desolvated.Crude product passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).This produces the target compound of 10 milligrams (theoretical values 8%).
LC-MS (method 2): R
t=2.41 min; MS (EIpos): m/z=468 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.17?(s,?3H),?3.81?(s,?3H),?6.50?(dd,?1H),?7.08?(mc,?1H),?7.25?(m,?1H).?7.30-7.34?(m,?2H),?7.37?(dd,?1H),?7.42?(d,?1H),?7.98?(dd,?1H),?8.05?(d,?1H),?8.11?(d,?1H),?8.89?(d,?1H),?8.91?(d,?1H),?9.07?(s,?1H)。
Embodiment 3A
Methyl-2-{[4-(quinoxalin-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-5-chlorobenzene carboxylicesters
With 80.0 milligrams of (0.254 mmole) embodiment 1A, 75.9 milligrams of (0.304 mmole) methyl-2-bromo-5-chloro-benzoic acid esters [Pan, Fletcher,
J. Med. Chem.1970,13,567] and 75.4 milligrams of (0.355 mmole) potassiumphosphates be dissolved in 2.0 milliliters of pure toluenes.Gained solution argon-degassed.Add subsequently 5.1 milligrams of (0.023 mmole) acid chlorides (II) and 10.2 milligrams of (0.034 mmole) (2-xenyls) two-
The tertiary butylPhosphine.It was stirred 72 hours under reflux temperature.Add 50 milliliters of ethyl acetate subsequently and remove solid residue by on diatomite, filtering.With gained filtrate evaporation concentration, crude product passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).This produces the target compound of 59 milligrams (theoretical values 48%).
LC-MS (method 2): R
t=2.56 min; MS (EIpos): m/z=484 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.19?(s,?3H),?2.49?(s,?3H),?3.81?(s,?3H),?6.50?(dd,?1H),?7.18-7.29?(m,?2H),?7.29-7.35?(m,?2H),?7.44?(d,?1H),?7.61?(d,?1H),?7.98?(dd,?1H),?8.06?(d,?1H),?8.13?(d,?1H),?8.89?(d,?1H),?8.91?(d,?1H),?9.21?(s,?1H)。
Embodiment 4A
Ethyl-2-{[4-(quinoxalin-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-5-methyl-benzoic ether
84.0 milligrams of (0.266 mmole) embodiment 1A, 77.7 milligrams of (0.320 mmole) ethyl-2-bromo-5-methyl benzoic acid esters and 79.2 milligrams of (0.373 mmole) potassiumphosphates are dissolved in 2.0 milliliters of pure toluenes.Gained solution argon-degassed.Add subsequently 5.4 milligrams of (0.024 mmole) acid chlorides (II) and 10.7 milligrams of (0.036 mmole) (2-xenyls) two-
The tertiary butylPhosphine.It was stirred 72 hours under reflux temperature.Add 50 milliliters of ethyl acetate subsequently and remove solid residue by on diatomite, filtering.With gained filtrate evaporation concentration, crude product passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).This produces the target compound of 18 milligrams (theoretical values 14%).
LC-MS (method 3): R
t=2.45 min; MS (EIpos): m/z=478 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?1.27?(t,?3H),?2.04?(s,?3H),?2.17?(s,?3H),?2.48?(s,?3H),?4.24?(q,?2H),?6.40?(d,?1H),?6.98?(dd,?1H),?7.24?(m,?1H),?7.30-7.34?(m,?2H),?7.41?(d,?1H),?7.48?(d,?1H),?7.98?(dd,?1H),?8.04?(d,?1H),?8.11?(d,?1H),?8.88?(d,?1H),?8.90?(d,?1H),?9.10?(s,?1H)。
Embodiment 5A
Methyl-2-{[4-(quinoxalin-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-l] amino } benzoic ether
84.0 milligrams of (0.266 mmole) embodiment 1A, 68.7 milligrams of (0.320 mmole) methyl-2-bromo-benzoates and 79.2 milligrams of (0.373 mmole) potassiumphosphates are dissolved in 2.0 milliliters of pure toluenes.Gained solution argon-degassed.Add subsequently 5.4 milligrams of (0.024 mmole) acid chlorides (II) and 10.7 milligrams of (0.036 mmole) (2-xenyls) two-
The tertiary butylPhosphine.It was stirred 48 hours under reflux temperature.Add 50 milliliters of ethyl acetate subsequently and remove solid residue by on diatomite, filtering.With gained filtrate evaporation concentration, crude product passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).This produces the target compound of 27 milligrams (theoretical values 23%).
LC-MS (method 3): R
t=2.18 min; MS (EIpos): m/z=450 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.18?(s,?3H),?2.48?(s,?3H),?3.80?(s,?3H),?6.48?(dd,?1H),?6.59?(mc,?1H),?7.14?(mc,?1H),?7.24?(mc,?1H),?7.28-7-34?(m,?2H),?7.43?(d,?1H),?7.66?(dd,?1H),?7.98?(dd,?1H),?8.04?(d,?1H),?8.12?(d,?1H),?8.87?(d,?1H),?8.89?(d,?1H),?9.23?(s,?1H)。
Embodiment 6A
Methyl-2-{[1-(2-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino }-5-methoxybenzoic acid ester
With 1.00 gram (4.185 mmole) 1-(2-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-5-amine [people such as Ochiai,
Chem. Pharm. Bull.2004,52,1098], 1.46 gram (5.779 mmole) methyl-2-bromo-5-methoxybenzoic acid esters and 1.43 gram (6.741 mmole) potassiumphosphates are dissolved in 50 milliliters of pure toluenes.Gained solution argon-degassed.Add subsequently 97 milligrams of (0.433 mmole) acid chlorides (II) and 194 milligrams of (0.650 mmole) (2-xenyls) two-
The tertiary butylPhosphine.It was stirred 72 hours under reflux temperature.With this mixture evaporation concentration and by MPLC purification (Puriflash Analogix:40M: isohexane/ethyl acetate=7/1).This produces the target compound of 211 milligrams (theoretical values 13%).
LC-MS (method 3): R
t=2.17 min; MS (EIpos): m/z=372 [M+H]
+
Embodiment 7A
Methyl-2-{[4-bromo-1-(2-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino }-5-methoxybenzoic acid ester
Be dissolved in 208 milligrams of (0.560 mmole) embodiment 6A in 3 milliliters of acetonitriles and add 105 milligrams of (0.588 mmole) N-bromosuccinimides.Keep 50 ℃ temperature 10 minutes and in rotatory evaporator, remove volatile constituent.It passes through preparation HPLC subsequently purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).This produces the target compound of 95 milligrams (theoretical values 38%).
LC-MS (method 3): R
t=2.45 min; MS (EIpos): m/z=450 [M]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.25?(s,?3H),?3.68?(s,?3H),?3.81?(s,?3H),?6.56?(d,?1H),?7.06?(dd,?1H),?7.26?(d,?1H),?7.41-7-52?(m,?2H),?7.59-7.65?(m,?2H),?8.75?(s,?1H)。
Embodiment 8A
Methyl-2-{[4-(quinoxalin-6-yl)-1-(2-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino }-5-methoxyl group-benzoic ether
95.0 milligrams of (0.211 mmole) embodiment 7A and 88.7 milligrams of (0.422 mmole) quinoxalin-6-yl borate hydrochlorates are dissolved among 15 milliliters of DMF.After adding 200 microlitres (0.400 mmole) 2M sodium carbonate solution, it is used argon-degassed.Add 14.6 milligrams of (0.013 mmoles) four (triphenyl phosphine) palladiums (0) and keep 110 ℃ temperature 1 hour.Recording by LC-MS after reaction finishes, adds 20 milliliters of ethyl acetate and remove solid residue by filtration on diatomite.Gained solution washs with 20 ml waters with 20 milliliters of saturated sodium-chloride water solutions.Organic phase is removed through dried over sodium sulfate and in rotatory evaporator and is desolvated.Crude product passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).This produces the target compound of 50 milligrams (theoretical values 47%).
LC-MS (method 1): R
t=2.47 min; MS (EIpos): m/z=500 [M+H]
+
Embodiment 9A
1-(2-aminomethyl phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-amine
Be dissolved in 5.00 gram (31.5 mmole) (2-aminomethyl phenyl) hydrazonium salt hydrochlorates in 30 milliliters of 1N hydrochloric acid and add 4.55 gram (33.4 mmole) 3-amino-4,4,4-trifluoro but-2-ene nitrile [the synthetic Krespan that is similar to,
J. Org. Chem.1969,34,42].With its stirred overnight under reflux temperature, subsequently with the alkalization of 1N sodium hydroxide solution.After ethyl acetate extraction (200 milliliters of 2 x), merge organic phase and through dried over mgso.In rotatory evaporator, remove volatile constituent and gained oil is dry under high vacuum.This produces the target compound of 6.85 grams (theoretical value 90%).
LC-MS (method 4): R
t=1.08 min; MS (EIpos): m/z=242 [M]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.03?(s,?3H),?5.47?(sbr,?2H),?5.72?(s,?1H),?7.30?(d,?1H),?7.35?(dt,?1H),?7.39-7.48?(m,?2H)。
Embodiment 10A
Methyl-5-chloro-2-{[1-(2-aminomethyl phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] amino } benzoic ether
1.50 gram (6.22 mmole) embodiment 9A, 1.86 gram (7.46 mmole) methyl-2-bromo-5-chloro-benzoic acid esters and 1.84 gram (8.71 mmole) potassiumphosphates are dissolved in 75 milliliters of pure toluenes.Gained solution argon-degassed.Add subsequently 126 milligrams of (0.560 mmole) acid chlorides (II) and 251 milligrams of (0.839 mmole) (2-xenyls) two-
The tertiary butylPhosphine.With its stirred overnight under reflux temperature.Reaction test shows, reacts incomplete.Therefore, add again 1.86 gram (7.46 mmole) methyl-2-bromo-5-chloro-benzoic acid esters and 126 milligrams of (0.560 mmole) acid chlorides (II) and 251 milligrams of (0.839 mmole) (2-xenyls) two-
The tertiary butylPhosphine.It is kept whole night under reflux temperature again.With this mixture evaporation concentration and by MPLC purification (Puriflash Analogix:40M: isohexane/ethyl acetate=9/1).This produces the target compound of 379 milligrams (theoretical values 12%), 80% purity (LC-MS cut).
LC-MS (method 1): R
t=3.15 min; MS (EIpos): m/z=410 [M+H]
+
Embodiment 11A
Methyl-5-chloro-2-{[4-iodo-1-(2-aminomethyl phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] amino } the benzene carboxylic acid ester
Be dissolved in 379 milligrams of (0.925 mmole) embodiment 10A in 8 milliliters of acetonitriles and add 218 milligrams of (0.971 mmole) N-iodosuccinimides.It is kept whole night under reflux temperature.Show by the LC/MS inspection, react incomplete.Therefore, add 208 milligrams of (0.925 mmole) N-iodosuccinimides and with its stirred overnight under reflux temperature.Add rare sodium sulfite solution (50 milliliters) and it is used ethyl acetate extraction (50 milliliters of 2 x).The organic phase that merges is through dried over mgso.In rotatory evaporator, remove volatile constituent, it passes through preparation HPLC subsequently purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).This produces the target compound of 277 milligrams (theoretical values 45%).
LC-MS (method 3): R
t=2.89 min; MS (EIpos): m/z=536 [M+H]
+
Embodiment 12A
1-(2-ethylphenyl)-3-methyl isophthalic acid H-pyrazoles-5-amine
2.000 gram (11.584 mmole) 2-ethylphenyl hydrazonium salt hydrochlorates are placed 10 milliliters of 1N hydrochloric acid and add the amino Ba Dousuan nitrile of 1.008 gram (12.279 mmole) 3-.This mixture stirred 18 hours down at 100 ℃.After cooling, the pH value of this mixture is adjusted to pH with the 1N sodium hydroxide solution〉12.It is used dichloromethane extraction three times.The organic phase that merges is washed with saturated sodium-chloride water solution, through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.Product is dry under high vacuum.We obtain the target compound of 2.354 grams (theoretical value 94%).
LC-MS (method 2): R
t=1.04 min; MS (EIpos): m/z=202 [M+H]
+
Embodiment 13A
Methyl-2-{[1-(2-ethylphenyl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino }-5-methoxybenzoic acid ester
Under argon atmospher, with 1.260 grams (6.260 mmole) from the compound dissolution of embodiment 12A in 12 milliliters of toluene, and add 1.279 gram (5.217 mmole) methyl-2-bromo-5-methoxybenzoic acid esters, 1.551 gram (7.303 mmole) potassiumphosphates, 0.210 gram (0.704 mmole) (2-xenyl) two-
The tertiary butylPhosphine and 0.105 gram (0.470 mmole) acid chloride (II).This mixture seethes with excitement whole night under refluxing.After cooling, it uses ethyl acetate extraction.The organic phase that merges washes with water, through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain 675 milligrams (theoretical values 30%).
LC-MS (method 3): R
t=2.30 min; MS (EIpos): m/z=366 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?0.98?(t,?3H),?2.21?(s,?3H),?2.36?(q,?2H),?3.71?(s,?6H),?6.10?(s,?1H),?7.17?(dd,?1H),?7.27-7.36?(m,?4H),?7.42-7-48?(m,?2H),?8.94?(s,?1H)。
Embodiment 14A
Methyl-2-{[4-bromo-1-(2-ethylphenyl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino }-5-methoxybenzoic acid ester
With 675 milligrams (1.847 mmoles) from the compound dissolution of embodiment 13A in 10 milliliters of methylene dichloride, and under 0-5 ℃, add 264 milligrams of (0.924 mmoles) 1,3-two bromo-5-5 T10s.Stir after 20 minutes, make it be warming up to room temperature.Add methylene dichloride, and with organic phase with twice of 10% sodium thiosulfate solution and saturated sodium-chloride water solution and water washing.Organic phase through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.The gained residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 814 milligrams (theoretical values 99%).
LC-MS (method 2): R
t=2.70 min; MS (EIpos): m/z=444 [M+H]
+
Embodiment 15A
Methyl-2-{[4-(quinoxalin-6-yl)-1-(2-ethylphenyl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino }-5-methoxyl group-benzoic ether
Under argon atmospher, with 340 milligrams (0.765 mmoles) from the compound dissolution of embodiment 14A in 1.7 milliliters of dimethyl formamides, and add 484 milligrams of (2.299 mmole) quinoxalin-6-yl borate hydrochlorates and 1.9 milliliters of 2N aqueous sodium carbonates.Adding 53 milligrams of (0.046 mmoles) four (triphenyl-phosphine) palladiums (0) also heats this mixture 15 minutes down at 110 ℃.After cooling, it uses ethyl acetate extraction.The organic phase that merges washes with water, through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 494 milligrams (theoretical values 69%).
LC-MS (method 3): R
t=2.28 min; MS (EIpos): m/z=494 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?1.07?(t,?3H),?2.48?(s,?3H),?2.48?(q,?2H),?3.55?(s,?3H),?3.79?(s,?3H),?6.47?(d,?1H),?6.80?(dd,?1H),?7.13?(d,?1H),?7.24-7.29?(m,?1H),?7.37-7.40?(m,?3H),?7.96?(dd,?1H),?8.02?(d,?1H),?8.10?(d,?1H),?8.88?(d,?1H),?8.90?(d,?1H)?8.91?(s,?1H)。
Embodiment 16A
Methyl-5-ethyl-2-{[3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } benzoic ether
Under argon atmospher; with 550 milligrams of (2.936 mmole) 3-methyl isophthalic acids-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine (about the preparation; referring to WO 2004/050651; the 30th page) and 1100 milligrams of (3.523 mmole) methyl-5-ethyl-2-{[(trifluoromethyls) alkylsulfonyl] the oxygen base benzoic ether (about the preparation; referring to WO 2004/024081; the 120th page) be dissolved in 10 milliliters of dry toluenes, and add 872 milligrams of (4.110 mmole) potassiumphosphates and 59 milligrams of (0.264 mmole) acid chlorides (II) and 118 milligrams (0.396 mmole) (2-duplex phenyl) two-
The tertiary butylPhosphine.This reaction mixture seethes with excitement whole night under refluxing.After cooling, add entry and it is used ethyl acetate extraction.The organic phase that merges is filtered through dried over sodium sulfate and on silica gel.Organic phase concentrating under reduced pressure and residue in the rotatory evaporator (eluent: methylene chloride=100:1) of on silica gel, purifying.We obtain the target compound of 636 milligrams (theoretical values 61%).
LC-MS (method 4): R
t=1.52 min; MS (EIpos): m/z=350 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?1.12?(t,?3H),?2.03?(s,?3H),?2.23?(s,?3H),?2.52?(q,?2H),?3.72?(s,?3H),?6.16?(s,?1H),?7.22?(d,?1H)?7.29-7.40?(m,?5H),?7.66?(d,?1H),?9.14?(s,?1H)。
Embodiment 17A
Methyl-2-{[4-bromo-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-5-ethylamino benzonitrile acid esters
With 590 milligrams (1.690 mmoles) from the compound dissolution of embodiment 16A in 9 milliliters of methylene dichloride and on ice bath, cool off, so that temperature is 0-5 ℃.Adding 242 milligrams of (0.845 mmoles) 1,3-two bromo-5 behind the 5-T10, stir them 20 minutes down at 0-5 ℃.Add methylene dichloride and organic phase with twice of 10% sodium thiosulfate solution and saturated sodium-chloride water solution and water washing.Organic phase through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.We obtain the target compound of 708 milligrams (theoretical values 98%).
LC-MS (method 3): R
t=2.78 min; MS (EIpos): m/z=428 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?1.10?(t,?3H),?2.08?(s,?3H),?2.26?(s,?3H),?2.48?(q,?2H),?3.79?(s,?3H),?6.49?(d,?1H),?7.22-7.34?(m,?5H),?7.61?(d,?1H),?8.85?(s,?1H)。
Embodiment 18A
Methyl-2-{[4-(quinoxalin-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-5-ethylamino benzonitrile acid esters
Under argon atmospher, with 200 milligrams (0.467 mmoles) from the compound dissolution of embodiment 17A in 5 milliliters of dimethyl formamides and add 295 milligrams of (1.403 mmole) quinoxalin-6-yl borate hydrochlorates and 1.2 milliliters of 2N aqueous sodium carbonates.Adding 32 milligrams of (0.028 mmoles) four (triphenyl phosphine) palladiums (0) also stirs this mixture 40 minutes down at 110 ℃.After cooling, add entry and it is used ethyl acetate extraction.The organic phase that merges through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 110 milligrams (theoretical values 49%).
LC-MS (method 4): R
t=1.48 min; MS (EIpos): m/z=478 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?0.97?(t,?3H),?2.18?(s,?3H),?2.34?(q,?2H),?2.48?(s,?3H),?3.79?(s,?3H),?6.41?(d,?1H),?7.01?(dd,?1H),?7.22-7.27?(m,?1H),?7.29-7.34?(m,?3H),?7.42?(d,?1H),?7.48?(d,?1H),?7.97?(dd,?1H),?8.04?(d,?1H),?8.11?(d,?1H),?8.88?(d,?1H),?8.90?(d,?1H)?9.10?(s,?1H)。
Embodiment 19A
7-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl) pyrido [2,3-b] pyrazine
Under argon atmospher, 52 milligrams of (0.057 mmoles) three-(dibenzylidene-acetone)-two palladium (0) and 38 milligrams of (0.137 mmole) tricyclohexyl phosphines are dissolved in 5.8 milliliters of dioxanes.Add 266 milligrams of (1.047 mmoles) 4,4,4'4'5,5,5'5'-prestox-2,2'-two-1,3,2-two oxa-borines, 200 milligrams of (0.952 mmole) 7-bromopyridines also [2,3-b] pyrazine (be described in WO 2006/009734, the 59 page in) and 140 milligrams of (1.428 mmole) potassium acetates and with this mixture 80 ℃ of following stirred overnight.After cooling, reaction mixture is concentrating under reduced pressure in rotatory evaporator, and residue is dissolved in cyclohexane/ethyl acetate (among the v/v=1:1) and filter on silica gel.Throw aside cyclohexane/ethyl acetate mutually and with methylene chloride (the rinsing silica gel of v/v=10:1).Filtrate is concentrating under reduced pressure in rotatory evaporator.According to GC-MS, we obtain the crude product of 178 milligrams (theoretical values 38%), purity 52%.This crude product is without the further reaction of further purifying promptly.
GC-MS (method 8): R
t=7.29 min; MS (EIpos): m/z=257 [M]
+
Embodiment 20A
Methyl-5-methoxyl group-2-{[3-methyl isophthalic acid-(2-aminomethyl phenyl)-4-(pyrido [2,3-b] pyrazine-7-yl)-1H-pyrazoles-5-yl] amino } benzoic ether
Under argon atmospher, with 96 milligrams of (0.223 mmole) methyl-2-{[4-bromo-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino-5-methoxybenzoic acid ester (be described in WO 2005/112923, the 18 page in) and 172 milligrams (0.348 mmole) from the compound dissolution of embodiment 19A in 3.8 milliliters of dimethyl formamides and add 760 microlitre 2N aqueous sodium carbonates and 15 milligrams of (0.013 mmoles) four (triphenyl phosphine) palladiums (0).This mixture was stirred 20 minutes down at 110 ℃.After cooling, add entry and it is used ethyl acetate extraction.The organic phase that merges through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 61 milligrams (theoretical values 57%).
LC-MS (method 1): R
t=2.22 min; MS (EIpos): m/z=481 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.18?(s,?3H),?3.56?(s,?3H),?3.81?(s,?3H),?6.46?(d,?1H),?6.82?(dd,?1H),?7.14?(d,?1H),?7.24-7.29?(m,?1H),?7.31-7.35?(m,?2H),?7.42?(d,?1H),?8.53?(d,?1H),?8.95?(s,?1H),?9.03?(d,?1H),?9.07?(d,?1H),?9.28?(d,?1H)。
Embodiment 21A
Methyl-2-{[4-(1H-indazole-5-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-5-methoxybenzoic acid ester
Under argon atmospher, with 130 milligrams of (0.303 mmole) methyl-2-{[4-bromo-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-5-methoxybenzoic acid ester (be described in WO2005/112923, the 18th page in) and 313 milligrams (0.909 mmole)
The tertiary butyl-5-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl)-1H-indazole-1 carboxylicesters is dissolved in 3.2 milliliters of dimethyl formamides and adds 760 microlitre 2N aqueous sodium carbonates and 21 milligrams of (0.018 mmoles) four (triphenyl phosphine) palladiums (0).With this mixture 110 ℃ of following stirred overnight.After cooling, add entry and it is used ethyl acetate extraction.The organic phase that merges through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 20 milligrams (theoretical values 14%).
LC-MS (method 4): R
t=1.26 min; MS (EIpos): m/z=468 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.15?(s,?3H),?2.36?(s,?3H),?3.57?(s,?3H),?3.78?(s,?3H),?6.42?(d,?1H),?6.83?(dd,?1H),?7.11?(d,?1H),?7.20-7.24?(m,?1H),?7.27-7.32?(m,?2H),?7.35?(d,?1H),?7.39?(dd,?1H),?7.47?(d,?1H),?7.77?(s,?1H),?8.02?(s,?1H),?8.78?(s,?1H),?13.01?(s,?1H)。
Embodiment 22A
Methyl-2-{[4-(quinoline-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-5-methoxyl group-benzoic ether
Under argon atmospher, with 130 milligrams of (0.303 mmole) methyl-2-{[4-bromo-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-5-methoxybenzoic acid ester (be described in WO 2005/112923, the 18 page in) and 157 milligrams of (0.909 mmole) quinoline-6-ylboronic acids be dissolved in 3.2 milliliters of dimethyl formamides and add 760 microlitre 2N aqueous sodium carbonates and 21 milligrams of (0.018 mmoles) four (triphenyl phosphine) palladiums (0).This mixture was stirred 10 minutes down at 110 ℃.After cooling, add entry and it is used ethyl acetate extraction.The organic phase that merges through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 76 milligrams (theoretical values 52%).
LC-MS (method 3): R
t=1.96 min; MS (EIpos): m/z=479 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.16?(s,?3H),?2.45?(s,?3H),?3.55?(s,?3H),?3.80?(s,?3H),?6.43?(d,?1H),?6.81?(dd,?1H),?7.12?(d,?1H),?7.22-7.27?(m,?1H),?7.30-7.34?(m,?2H),?7.39?(d,?1H),?7.50?(dd,?1H),?7.83?(dd,?1H),?7.93?(d,?1H),?8.01?(d,?1H),?8.27?(d,?1H),?8.84?(dd,?1H),?8.88?(s,?1H)。
Embodiment 23A
Methyl-2-{[4-(1,3-benzothiazole-5-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-5-methoxybenzoic acid ester
Under argon atmospher, with 340 milligrams of (0.790 mmole) methyl-2-{[4-bromo-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-5-methoxybenzoic acid ester (is described in WO 2005/112923, in the 18th page) and 620 milligrams of (2.374 mmole) 5-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl)-1, the 3-benzothiazole is dissolved in 8.4 milliliters of dimethyl formamides and adds 1.975 milliliters of 2N aqueous sodium carbonates and 55 milligrams of (0.047 mmoles) four (triphenyl phosphine) palladiums (0).This mixture was stirred 15 minutes down at 110 ℃.After cooling, add entry and it is used ethyl acetate extraction.The organic phase that merges through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 60 milligrams (theoretical values 16%).
LC-MS (method 4): R
t=1.39 min; MS (EIpos): m/z=485 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.16?(s,?3H),?2.41?(s,?3H),?3.57?(s,?3H),?3.78?(s,?3H),?6.43?(d,?1H),?6.84?(dd,?1H),?7.13?(d,?1H),?7.20-7.25?(m,?1H),?7.28-7.32?(m,?2H),?7.38?(d,?1H),?7.56?(dd,?1H),?8.10-8.12?(m,?2H),?8.84?(s,?1H),?9.36?(s,?1H)。
Embodiment 24A
Methyl-5-methoxyl group-2-{[3-methyl isophthalic acid-(2-aminomethyl phenyl)-4-(naphthalene-2-yl)-1H-pyrazoles-5-yl] amino } benzoic ether
Under argon atmospher, with 340 milligrams of (0.790 mmole) methyl-2-{[4-bromo-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-5-methoxybenzoic acid ester (be described in WO 2005/112923, the 18 page in) and 408 milligrams of (2.374 mmole) naphthalene-2-ylboronic acids be dissolved in 8.4 milliliters of dimethyl formamides and add 1.975 milliliters of 2N aqueous sodium carbonates and 55 milligrams of (0.047 mmoles) four (triphenyl phosphine) palladiums (0).This mixture was stirred 15 minutes down at 110 ℃.After cooling, add entry and it is used ethyl acetate extraction.The organic phase that merges through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 23 milligrams (theoretical values 6%).
LC-MS (method 1): R
t=3.00 min; MS (EIpos): m/z=478 [M+H]
+
Embodiment 25A
4-bromo-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine
At room temperature, dropwise add (C. Alberti in 7.50 gram (43.3 mmole) 1-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine in 30 milliliters of acetate lentamente to being dissolved in 6.92 in 5 milliliters of acetate grams (43.3 mmole) bromine, C. Tironi, Farmaco 1967,22,58-75).After at room temperature stirring 30 minutes, 35 ml waters are added in this mixture, and refrigerative alkalizes with the potassium hydroxide powder simultaneously on ice bath.It is with each 50 milliliters of ethyl acetate extractions twice, and the organic phase of merging is through dried over mgso, subsequently evaporation concentration.This residue is purified as eluent with the cyclohexane/ethyl acetate of ratio 5:1 by the flash chromatography on silica gel method.This produces the target compounds (theoretical value 82%) of 9.00 grams.
LC-MS (method 4): R
t=0.94 min; MS (EIpos): m/z=252 [M+H]
+
1H?NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.04?(s,?3H),?5.19?(s,?2H),?7.24?(d,?1H),?7.29?-?7.36?(m,?1H),?7.36?-?7.43?(m,?3H)。
Embodiment 26A
4-(quinoxalin-6-yl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine
Under argon atmospher, add 1.50 gram (7.14 mmole) quinoxalin-6-yl borate hydrochlorates, 0.34 gram (0.30 mmole) four (triphenyl phosphine) palladium (0) and 10 milliliters of saturated aqueous sodium carbonates to 1.50 restraining in (5.95 mmole) 4-bromo-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine (embodiment 25A) in 15 milliliters of DMF.This mixture was stirred 3 hours down at 110 ℃, add to subsequently in 150 ml waters so that handle.It is with each 50 milliliters of ethyl acetate extractions twice, and the organic phase of merging is through dried over mgso, and evaporation concentration.In order to purify, with its chromatographic separation twice on silica gel, at first follow pure ethyl acetate as eluent with cyclohexane/ethyl acetate 2:1, follow 20:1 as solvent with methylene chloride 50:1 subsequently.Behind evaporation concentration product cut, we obtain 729 milligrams with triphenyl phosphine oxide compound blended target compound (according to LC-MS, 78%, be equivalent to 32% yield).
LC-MS (method 2): R
t=1.64 min; MS (EIpos): m/z=302 [M+H]
+
1H?NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.12?(s,?3H),?5.48?(m,?2H),?7.28?-?7.68?(m,?4H),?7.99?(s,?1H),?8.04?(d,?1H),?8.14?(dd,?1H),?8.18?(d,?1H),?8.82?(d,?1H),?8.89?(d,?1H)。
Embodiment 27A
Methyl-2-{[4-(quinoxalin-6-yl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } benzoic ether
Under argon atmospher, with 0.09 gram (0.22 mmole) acid chloride (II) add in 7 milliliters of toluene 720 milligrams (2.39 mmoles) from 4-(quinoxalin-6-yl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine of embodiment 26A, 617 milligrams of (2.87 mmole) methyl-2-bromo-benzoates, 710 milligrams of (3.35 mmole) potassiumphosphates and 96 milligrams of (0.32 mmole) 2-(two-
The tertiary butylPhosphino-)-biphenyl in, heating is whole night under refluxing with reaction mixture subsequently.at first add 10 milligrams of (0.04 mmole) acid chlorides (II) and add 10 milligrams of (0.04 mmole) acid chlorides (II) subsequently again and 25 milligrams of (0.08 mmole) 2-(two-
The tertiary butylPhosphino-)-biphenyl after, it is stirred overnight under refluxing once more in each case, with aftertreatment.For this reason, this mixture filters on diatomite, and the eluate that obtains with ethyl acetate washing back passes through evaporation concentration.After purifying, obtain 200 milligrams of target compounds (theoretical value 25%) thus by preparation HPLC method 7.
LC-MS (method 1): R
t=2.50 min; MS (EIpos): m/z=436 [M+H]
+
1H?NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.14?(s,?3H),?3.84?(s,?3H),?6.45?(d,?1H),?6.69?(t,?1H),?7.18?-?7.29?(m,?2H),?7.33?(d,?2H),?7.44?(d,?1H),?7.77?(dd,?1H),?8.05?(d,?1H),?8.20?(dd,?1H),?8.25?(d,?1H),?8.53?(s,?1H),?8.85?(d,?1H),?8.86?(d,?1H),?9.29?(s,?1H)。
Embodiment 28A
4-(quinoxalin-6-yl)-1-phenyl-1H-pyrazoles-5-amine
Under argon atmospher, with 848 milligrams of (4.03 mmole) quinoxalin-6-yl borate hydrochlorates, 78 milligrams of (0.067 mmoles) four (triphenyl phosphine) palladiums (0) and 4 milliliters of saturated aqueous sodium carbonates add 800 milligrams of (3.36 mmole) 4-bromo-1-in 8 milliliters of DMF to phenyl-(US 5201938 for 1H-pyrazoles-5-amine; Arch. Pharm. 1966,299, and 147) in.This mixture was stirred 4 hours down at 110 ℃, add to subsequently in 100 ml waters so that handle.It filters on diatomite and evaporation concentration with each 50 milliliters of ethyl acetate extractions twice, the organic phase of merging.In order to purify, with cyclohexane/ethyl acetate (at first with 5:1,2:1 ratio) subsequently, then pure ethyl acetate is as the eluent chromatographic separation on silica gel for it.Behind evaporation concentration product cut, we obtain thus 349 milligrams with triphenyl phosphine oxide compound blended target compound (according to LC-MS, 81%, be equivalent to 29% yield).
LC-MS (method 4): R
t=0.89 min; MS (EIpos): m/z=288 [M+H]
+
1H?NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?5.71?(s,?2H),?7.43?(t,?1H),?7.52?-?7.66?(m,?4H),?7.99?(s,?1H),?8.06?(d,?1H),?8.12?(dd,?1H),?8.19?(d,?1H),?8.84?(d,?1H),?8.90?(d,?1H)。
Embodiment 29A
Methyl-2-{[4-(quinoxalin-6-yl)-1-phenyl-1H-pyrazoles-5-yl] amino } benzoic ether
Under argon atmospher, with 24 milligrams of (0.11 mmole) acid chlorides (II) add in 4 milliliters of toluene 340 milligrams (1.18 mmoles) from 4-(quinoxalin-6-yl)-1-phenyl-1H-pyrazoles-5-amine of embodiment 28A, 254 milligrams of (1.18 mmole) methyl-2-bromo-benzoates, 352 milligrams of (1.66 mmole) potassiumphosphates and 48 milligrams of (0.16 mmole) 2-(two-
The tertiary butylPhosphino-)-biphenyl in, heating is whole night under refluxing with reaction mixture subsequently.After adding 10 milligrams of (0.04 mmole) acid chlorides (II) again, with its restir whole night twice under refluxing, with aftertreatment., this mixture is added in the water for this reason, use ethyl acetate extraction subsequently twice.Behind dried over mgso organic phase and evaporation concentration solvent, at first with ratio 5:1,2:1 follows pure ethyl acetate and purifies as eluent this residue subsequently by the flash chromatography on silica gel method.This produces 100 milligrams of target compounds (theoretical value 25%).
LC-MS (method 3): R
t=2.11 min; MS (EIpos): m/z=422 [M+H]
+
1H?NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?3.91?(s,?3H),?6.28?(d,?1H),?6.68?(t,?1H),?7.18?(td,?1H),?7.34?(t,?1H),?7.44?(t,?2H),?7.66?(d,?2H),?7.82?(dd,?1H),?8.05?(d,?1H),?8.19?(dd,?1H),?8.28?(d,?1H),?8.53?(s,?1H),?8.85?(d,?1H),?8.87?(d,?1H),?9.47?(s,?1H)。
Embodiment 30A
6-bromo-7-fluorine quinoxaline
With 3.300 gram (16.095 mmole) 4-bromo-5-fluorobenzene-1,2-diamines (being described in WO 2008/021851, the 75-76 page or leaf) is dissolved in 160 milliliters of ethanol and adds 1.933 grams (16.095 mmole)
Trans-2,3-dihydroxyl-1,4-dioxane.It was at room temperature stirred 2 hours and with reaction mixture in rotatory evaporator by evaporation concentration to 3/4.Leach the gained throw out and drying under high vacuum.We obtain the target compound of 2.950 grams (theoretical value 81%).
LC-MS (method 4): R
t=1.00 min; MS (EIpos): m/z=227 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?8.11?(d,?1H),?8.58?(d,?1H),?8.98-9.03?(m,?2H)。
Embodiment 31A
6-fluoro-7-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl) quinoxaline
Under argon atmospher, 714 milligrams of (0.780 mmoles) three-(dibenzylidene-acetone)-two palladium (0) and 525 milligrams of (1.871 mmole) tricyclohexyl phosphines are dissolved in 80 milliliters of dioxanes.Add 3630 milligrams of (14.293 mmoles) 4,4,4'4'5,5,5'5'-prestox-2,2'-two-1,3,2-two oxa-borines, 2950 milligrams (12.993 mmole) are from compound and 1913 milligrams of (19.490 mmole) potassium acetates of embodiment 30A, and with this mixture 80 ℃ of following stirred overnight.After cooling, dioxane added in the reaction mixture and with it on diatomite, filter.Filtrate is concentrating under reduced pressure and dry under high vacuum in rotatory evaporator.We obtain 6530 milligrams of crude products (according to GC-MS, purity about 30%), and it is without the further reaction of further purifying promptly.
GC-MS (method 6): R
t=6.57 min; MS (EIpos): m/z=274 [M]
+
Embodiment 32A
Methyl-2-{[4-(7-fluorine quinoxalin-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-5-methoxybenzoic acid ester
Under argon atmospher, with 350 milligrams of (0.813 mmole) methyl-2-{[4-bromo-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-5-methoxybenzoic acid ester (is described in WO 2005/112923, in the 18th page) and 3000 milligrams (about 3.283 mmoles) from the compound dissolution of embodiment 31A in 9.000 milliliters of dimethyl formamides, and add 2.033 milliliters of 2N aqueous sodium carbonates and 56 milligrams of (0.049 mmoles) four (triphenyl phosphine) palladiums (0).This mixture was stirred 3 hours down at 110 ℃.After cooling, add entry and it is used ethyl acetate extraction.The organic phase that merges through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 164 milligrams (purity 40%, theoretical value 16%).
LC-MS (method 4): R
t=1.35 min; MS (EIpos): m/z=498 [M+H]
+
Embodiment 33A
4-bromo-5-chloro-2-N-methyl-p-nitroaniline
6.00 gram (34.768 mmole) 5-chloro-2-N-methyl-p-nitroanilines and 6.06 gram (34.073 mmole) N-bromosuccinimides are dissolved in 240 milliliters of acetate.This mixture seethed with excitement 45 minutes under refluxing.After cooling, reaction mixture is added in 1.5 premium on currency.Leach the gained throw out and drying under high vacuum.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 6.75 grams (theoretical value 75%).
LC-MS (method 4): R
t=1.19 min; MS (EImin): m/z=249 [M-H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?7.29?(s,?1H),?7.62?(sbr,?2H),?8.24?(s,?1H)。
Embodiment 34A
4-bromo-5-chlorobenzene-1, the 2-diamines
With 5.00 grams (19.883 mmole) from the compound dissolution of embodiment 33A in 120 milliliters of ethanol and add 17.95 gram (79.531 mmole) two hydration tin chlorides (II).With this mixture 70 ℃ of following stirred overnight.After cooling, add entry, make it be weakly alkaline with saturated sodium bicarbonate aqueous solution and also use ethyl acetate extraction three times.The organic phase that merges through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.This residue is dry under high vacuum.We obtain the target compound of 4.25 grams (purity 77%, theoretical value 74%).
LC-MS (method 3): R
t=1.36 min; MS (EIpos): m/z=221 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?4.85?(s,?2H),?4.89?(s,?2H),?6.64?(s,?1H),?6.75?(s,?1H)。
Embodiment 35A
6-bromo-7-chloro-quinoxaline
With 4.25 grams (about 14.775 mmoles) from the compound dissolution of embodiment 34A in 200 milliliters of ethanol and add 2.30 grams (19.188 mmole)
Trans-2,3-dihydroxyl-1,4-dioxane.With its stirred overnight and make this mixture leave standstill a weekend at room temperature.The product that crystallization is gone out leaches and drying under high vacuum.We obtain the target compound of 3.33 grams (theoretical value 94%).
LC-MS (method 3): R
t=1.77 min; MS (EIpos): m/z=243 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?8.43?(s,?1H),?8.59?(s,?1H),?9.01?(d,?1H),?9.03?(d,?1H)。
Embodiment 36A
6-chloro-7-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl) quinoxaline
Under argon atmospher, 741 milligrams of (0.809 mmoles) three-(dibenzylidene-acetone)-two palladium (0) and 545 milligrams of (1.943 mmole) tricyclohexyl phosphines are dissolved in 80 milliliters of dioxanes.Add 3769 milligrams of (14.840 mmoles) 4,4,4'4'5,5,5'5'-prestox-2,2'-is two-1,3,2-two oxa-borines, 3285 milligrams (13.491 mmole) from the compound of embodiment 35A and 1986 milligrams of (20.236 mmole) potassium acetates and with this mixture 80 ℃ of following stirred overnight.After cooling, dioxane added in this reaction mixture and with it on diatomite, filter.Filtrate is concentrating under reduced pressure and dry under high vacuum in rotatory evaporator.We obtain 7300 milligrams of crude products (according to GC-MS, purity about 18%), and it is without the further reaction of further purifying promptly.
GC-MS (method 6): R
t=7.22 min; MS (EIpos): m/z=290 [M]
+
Embodiment 37A
Methyl-2-{[4-(7-chloro-quinoxaline-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-5-methoxybenzoic acid ester
Under argon atmospher, with 350 milligrams of (0.813 mmole) methyl-2-{[4-bromo-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino-5-methoxybenzoic acid ester (be described in WO 2005/112923, the 18 page in) and 4000 milligrams (about 2.478 mmoles) from the compound dissolution of embodiment 36A in 11.000 milliliters of dimethyl formamides and add 2.033 milliliters of 2N aqueous sodium carbonates and 56 milligrams of (0.049 mmoles) four (triphenyl phosphine) palladiums (0).This mixture was stirred 3 hours down at 110 ℃.After cooling, add entry and it is used ethyl acetate extraction.The organic phase that merges through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 36 milligrams (purity 81%, theoretical value 7%).
LC-MS (method 1): R
t=2.66 min; MS (EIpos): m/z=514 [M+H]
+
Embodiment 38A
4-bromo-5-methyl-2-N-methyl-p-nitroaniline
5.00 gram (32.861 mmole) 5-methyl-2-N-methyl-p-nitroanilines and 5.73 gram (32.204 mmole) N-bromosuccinimides are dissolved in 225 milliliters of acetate.This mixture seethed with excitement 90 minutes under refluxing.After cooling, reaction mixture is added in 1.5 premium on currency.Leach the gained throw out and drying under high vacuum.We obtain the target compound of 6.65 grams (theoretical value 84%).
LC-MS (method 1): R
t=2.23 min; MS (EIpos): m/z=231 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.27?(s,?3H),?6.98?(s,?1H),?7.48?(sbr,?2H),?8.09?(s,?1H)。
Embodiment 39A
4-bromo-5-methylbenzene-1, the 2-diamines
With 4.00 grams (17.312 mmole) from the compound dissolution of embodiment 38A in 100 milliliters of ethanol and add 15.63 gram (69.248 mmole) two hydration tin chlorides (II).With this mixture 70 ℃ of following stirred overnight.After cooling, add entry, make it be weakly alkaline with saturated sodium bicarbonate aqueous solution and also use ethyl acetate extraction three times.The organic phase that merges through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.This residue is dry under high vacuum.We obtain the target compound of 3.23 grams (theoretical value 89%).
LC-MS (method 1): R
t=1.07 min; MS (EIpos): m/z=201 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.08?(s,?3H),?4.51?(s,?2H),?4.52?(s,?2H),?6.43?(s,?1H),?6.66?(s,?1H)。
Embodiment 40A
6-bromo-7-methyl-quinoxaline
With 1.00 grams (4.973 mmole) from the compound dissolution of embodiment 39A in 50 milliliters of ethanol and add 0.59 gram (4.973 mmole)
Trans-2,3-dihydroxyl-1,4-dioxane.With its stirred overnight at room temperature.Reaction mixture is concentrating under reduced pressure in rotatory evaporator, is dissolved in the ethyl acetate and on silica gel to purify.We obtain the target compound of 994 milligrams (theoretical values 84%).
LC-MS (method 3): R
t=1.65 min; MS (EIpos): m/z=224 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.60?(s,?3H),?8.11?(s,?1H),?8.39?(s,?1H),?8.92?(d,?1H),?8.96?(d,?1H)。
Embodiment 41A
6-methyl-7-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl) quinoxaline
Under argon atmospher, 243 milligrams of (0.265 mmoles) three-(dibenzylidene-acetone)-two palladium (0) and 179 milligrams of (0.637 mmole) tricyclohexyl phosphines are dissolved in 30 milliliters of dioxanes.Add 1236 milligrams of (4.865 mmoles) 4,4,4'4'5,5,5'5'-prestox-2,2'-is two-1,3,2-two oxa-borines, 987 milligrams (4.423 mmole) from the compound of embodiment 40A and 651 milligrams of (6.635 mmole) potassium acetates and with this mixture 80 ℃ of following stirred overnight.After cooling, dioxane added in the reaction mixture and with it on diatomite, filter.Filtrate is concentrating under reduced pressure and dry under high vacuum in rotatory evaporator.We obtain 2321 milligrams of crude products (according to LC-MS, purity 42%, theoretical value 82%), it is without the further reaction of further purifying promptly.
GC-MS (method 6): R
t=7.01 min; MS (EIpos): m/z=270 [M]
+
Embodiment 42A
Methyl-5-methoxyl group-2-{[3-methyl-4-(7-methyl-quinoxaline-6-yl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } benzoic ether
Under argon atmospher, with 350 milligrams of (0.813 mmole) methyl-2-{[4-bromo-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino-5-methoxybenzoic acid ester (be described in WO 2005/112923, the 18 page in) and 2321 milligrams (about 3.608 mmoles) from the compound dissolution of embodiment 41A in 20.000 milliliters of dimethyl formamides and add 2.033 milliliters of 2N aqueous sodium carbonates and 56 milligrams of (0.049 mmoles) four (triphenyl phosphine) palladiums (0).This mixture was stirred 3 hours down at 110 ℃.After cooling, add entry and it is used ethyl acetate extraction.The organic phase that merges through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 36 milligrams (purity 88%, theoretical value 31%).
LC-MS (method 3): R
t=2.18 min; MS (EIpos): m/z=494 [M+H]
+
Embodiment 43A
4-bromo-3-chloro-2-N-methyl-p-nitroaniline
5.00 gram (28.973 mmole) 3-chloro-2-N-methyl-p-nitroanilines and 5.05 gram (28.394 mmole) N-bromosuccinimides are dissolved in 250 milliliters of acetate.This mixture seethed with excitement 45 minutes under refluxing.After cooling, reaction mixture is added in 1.5 premium on currency.Leach the gained throw out and drying under high vacuum.We obtain the target compound of 5.25 grams (theoretical value 72%).
LC-MS (method 9): R
t=2.16 min; MS (EImin): m/z=251 [M-H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?6.40?(sbr,?2H),?6.83?(d,?1H),?7.56?(d,?1H)。
Embodiment 44A
4-bromo-3-chlorobenzene-1, the 2-diamines
With 5.25 grams (20.877 mmole) from the compound dissolution of embodiment 43A in 120 milliliters of ethanol and add 18.84 gram (83.508 mmole) two hydration tin chlorides (II).With this mixture 70 ℃ of following stirred overnight.After cooling, add entry, make it be weakly alkaline with saturated sodium bicarbonate aqueous solution and also use ethyl acetate extraction three times.The organic phase that merges through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.This residue is dry under high vacuum.We obtain the target compound of 4.40 grams (purity 74%, theoretical value 70%).
LC-MS (method 3): R
t=1.42 min; MS (EIpos): m/z=221 [M+H]
+
Embodiment 45A
6-bromo-5-chloro-quinoxaline
With 4.40 grams (about 14.700 mmoles) from the compound dissolution of embodiment 44A in 200 milliliters of ethanol and add 2.39 grams (19.865 mmole)
Trans-2,3-dihydroxyl-1,4-dioxane.With its stirred overnight at room temperature.With this reaction mixture evaporation concentration to 2/3, the product that crystallization is gone out leaches, with small amount of ethanol washing and dry under high vacuum.We obtain the target compound of 3.33 grams (theoretical value 89%).
LC-MS (method 4): R
t=1.04 min; MS (EIpos): m/z=243 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?8.04?(d,?1H),?8.19?(d,?1H),?9.09?(d,?1H),?9.10?(d,?1H)。
Embodiment 46A
5-chloro-6-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl) quinoxaline
Under argon atmospher, 722 milligrams of (0.789 mmoles) three-(dibenzylidene-acetone)-two palladium (0) and 531 milligrams of (1.892 mmole) tricyclohexyl phosphines are dissolved in 80 milliliters of dioxanes.Add 3671 milligrams of (14.456 mmoles) 4,4,4'4'5,5,5'5'-prestox-2,2'-is two-1,3,2-two oxa-borines, 3200 milligrams (13.142 mmole) from the compound of embodiment 45A and 1935 milligrams of (19.713 mmole) potassium acetates and with this mixture 80 ℃ of following stirred overnight.After cooling, dioxane added in the reaction mixture and with it on diatomite, filter.Filtrate is concentrating under reduced pressure and dry under high vacuum in rotatory evaporator.We obtain 7520 milligrams of crude products (according to GC-MS, purity 57%), and it is without the further reaction of further purifying promptly.
GC-MS (method 6): R
t=7.54 min; MS (EIpos): m/z=290 [M]
+
Embodiment 47A
Methyl-2-{[4-(5-chloro-quinoxaline-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-5-methoxybenzoic acid ester
Under argon atmospher, with 350 milligrams of (0.813 mmole) methyl-2-{[4-bromo-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino-5-methoxybenzoic acid ester (be described in WO 2005/112923, the 18 page in) and 3000 milligrams (about 5.885 mmoles) from the compound dissolution of embodiment 46A in 10.000 milliliters of dimethyl formamides and add 2.033 milliliters of 2N aqueous sodium carbonates and 56 milligrams of (0.049 mmoles) four (triphenyl phosphine) palladiums (0).This mixture was stirred 3 hours down at 110 ℃.After cooling, add entry and it is used ethyl acetate extraction.The organic phase that merges through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 172 milligrams (purity 50%, theoretical value 21%).
LC-MS (method 3): R
t=2.19 min; MS (EIpos): m/z=514 [M+H]
+
Embodiment 48A
N-(5-bromopyridine-2-yl)-N'-hydroxyl acylimino methane amide
Be suspended in 10.00 gram (57.797 mmole) 2-amino-5-bromopyridines in 20 milliliters of Virahols and at room temperature dropwise add 10.05 milliliters of (75.137 mmole) dimethyl formamide-dimethylacetals.This mixture seethed with excitement 3 hours under refluxing.It is cooled to 50 ℃, add 5.221 gram (75.137 mmole) hydroxylamine hydrochlorides and with it 50 ℃ of following stirred overnight.After cooling, reaction mixture concentrates in rotatory evaporator.Crude product passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 10.20 grams (theoretical value 82%).
LC-MS (method 4): R
t=0.78 min; MS (EIpos): m/z=216 [M+H]
+
Embodiment 49A
6-bromine [1,2,4] triazolo [1,5-a] pyridine
Be suspended in 60 milliliter THFs from the compound of embodiment 48A 6.00 grams (27.772 mmole) and on ice bath, cool off.In 5-10 minute, dropwise add 6.42 gram (30.549 mmole) trifluoroacetic anhydrides, so that internal temperature is no more than 20 ℃.Remove ice bath and it was at room temperature stirred 3.5 hours.After adding 150 milliliter of 5% sodium bicarbonate aqueous solution, it is extracted three times with t-butyl methyl ether.The organic phase that merges is washed with a small amount of 5% sodium bicarbonate aqueous solution, concentrates through dried over sodium sulfate and in rotatory evaporator.We obtain the target compound of 4.60 grams (theoretical value 84%).
LC-MS (method 1): R
t=1.15 min; MS (EIpos): m/z=198 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?7.82?(dd,?1H),?7.86?(d,?1H),?8.54?(s,?1H),?9.41?(m,?1H)。
Embodiment 50A
Methyl-5-methoxyl group-2-{[3-methyl isophthalic acid-(2-aminomethyl phenyl)-4-([1,2,4] triazolo [1,5-a] pyridine-6-yl)-1H-pyrazoles-5-yl] amino } benzoic ether
Under argon atmospher, 277 milligrams of (0.303 mmoles) three-(dibenzylidene-acetone)-two palladium (0) and 224 milligrams of (0.727 mmole) tricyclohexyl phosphines are dissolved in 30 milliliters of dioxanes.Add 1410 milligrams of (5.555 mmoles) 4,4,4'4'5,5,5'5'-prestox-2,2'-is two-1,3,2-two oxa-borines, 1000 milligrams (5.050 mmole) from the compound of embodiment 49A and 743 milligrams of (7.575 mmole) potassium acetates and with this mixture 80 ℃ of following stirred overnight.After cooling, dioxane added in the reaction mixture and with it on diatomite, filter.Filtrate is concentrating under reduced pressure and dry under high vacuum in rotatory evaporator.We obtain 2520 milligrams of 6-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl) [1,2,4] triazolo [1,5-a] pyridine as crude product, and it is without the further reaction of further purifying promptly.
Under argon atmospher, with 350 milligrams of (0.813 mmole) methyl-2-{[4-bromo-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-5-methoxybenzoic acid ester (is described in WO 2005/112923, in the 18th page) and 2279 milligrams of 6-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl) [1,2,4] triazolo [1,5-a] pyridine (crude product) is dissolved in 13.000 milliliters of dimethyl formamides and adds 2.033 milliliters of 2N aqueous sodium carbonates and 56 milligrams of (0.049 mmoles) four (triphenyl phosphine) palladiums (0).This mixture was stirred 2 hours down at 110 ℃.After cooling, add entry and it is used ethyl acetate extraction.The organic phase that merges through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water+0.5% TFA, gradient 10:90 → 90:10).We obtain the target compound of 198 milligrams (theoretical values 52%).
LC-MS (method 4): R
t=1.20 min; MS (EIpos): m/z=469 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.16?(s,?3H),?2.40?(s,?3H),?3.57?(s,?3H),?3.79?(s,?3H),?6.43?(d,?1H),?6.85?(dd,?1H),?7.13?(d,?1H),?7.21-7.26?(m,?1H),?7.29-7.35?(m,?3H),?7.75?(dd,?1H),?7.81?(d,?1H),?8.47?(s,?1H),?8.83?(s,?1H),?9.03?(sbr,?1H)。
Embodiment 51A
1-(2-p-methoxy-phenyl)-3-methyl isophthalic acid H-pyrazoles-5-amine
2.000 gram (11.453 mmole) 2-p-methoxy-phenyl hydrazonium salt hydrochlorates are placed 10 milliliters of 1N hydrochloric acid and add the amino propenyl cyanide of 0.997 gram (12.140 mmole) 3-.This mixture was stirred 18 hours down at 100 ℃.After cooling, the pH value of this mixture is adjusted to pH with the 1N sodium hydroxide solution〉12.It is used dichloromethane extraction three times.The organic phase that merges is washed with saturated sodium-chloride water solution, through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.Product is dry under high vacuum.We obtain the target compound of 2.430 grams (according to the purity 91% of LC-MS, theoretical value 95%).
LC-MS (method 3): R
t=0.31 min; MS (EIpos): m/z=204 [M+H]
+
Embodiment 52A
Methyl-5-methoxyl group-2-{[1-(2-p-methoxy-phenyl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino } benzoic ether
Under argon atmospher, with 2.300 grams (about 10.298 mmoles) from the compound dissolution of embodiment 51A in 20 milliliters of toluene and add 2.103 gram (8.585 mmole) methyl-2-bromo-5-methoxybenzoic acid esters, 2.551 gram (12.014 mmole) potassiumphosphates, 0.346 gram (1.159 mmole) (2-xenyl) two-
The tertiary butylPhosphine and 0.173 gram (0.772 mmole) acid chloride (II).This mixture seethes with excitement whole night under refluxing.After cooling, it uses ethyl acetate extraction.The organic phase that merges washes with water, through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain 135 milligrams (theoretical values 4%).
LC-MS (method 4): R
t=1.28 min; MS (EIpos): m/z=368 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.20?(s,?3H),?3.70?(s,?3H),?3.80?(s,?3H),?3.84?(s,?3H),?6.07?(s,?1H),?7.04?(dt,?1H),?7.11?(dd,?1H),?7.16-7.24?(m,?2H),?7.30?(d,?1H),?7.34?(dd,?1H),?7.41-7.46?(m,?1H),?9.14?(sbr,?1H)。
Embodiment 53A
Methyl-2-{[4-bromo-1-(2-p-methoxy-phenyl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino }-5-methoxybenzoic acid ester
With 132 milligrams (0.359 mmoles) from the compound dissolution of embodiment 52A in 2 milliliters of methylene dichloride, and under 0-5 ℃, add 51 milligrams of (0.180 mmoles) 1,3-two bromo-5,5-T10.Stir after 20 minutes, make it be warming up to room temperature.Add methylene dichloride and with organic phase with twice of 10% sodium thiosulfate solution and saturated sodium-chloride water solution and water washing.Organic phase through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.We obtain the target compound of 148 milligrams (theoretical values 92%).
LC-MS (method 4): R
t=1.41 min; MS (EIpos): m/z=446 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.23?(s,?3H),?3.67?(s,?3H),?3.82?(s,?3H),?3.83?(s,?3H),?7.02?(dt,?1H),?7.06?(dd,?1H),?7.18?(d,?1H),?7.27?(d,?1H),?7.36?(dd,?1H),?7.39-7.44?(m,?1H),?8.88?(sbr,?1H)。
Embodiment 54A
Methyl-2-{[4-(quinoxalin-6-yl)-1-(2-p-methoxy-phenyl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino }-5-methoxybenzoic acid ester
Under argon atmospher, with 145 milligrams (0.325 mmoles) from the compound dissolution of embodiment 53A in 3.5 milliliters of dimethyl formamides and add 205 milligrams of (0.976 mmole) quinoxalin-6-yl borate hydrochlorates and 0.8 milliliter of 2N aqueous sodium carbonate.Adding 23 milligrams of (0.019 mmoles) four (triphenyl phosphine) palladiums (0) also heats this mixture 15 minutes down at 110 ℃.After cooling, it uses ethyl acetate extraction.The organic phase that merges washes with water, through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 94 milligrams (theoretical values 58%).
LC-MS (method 4): R
t=1.26 min; MS (EIpos): m/z=496 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.46?(s,?3H),?3.53?(s,?3H),?3.84?(s,?3H),?3.86?(s,?3H),?6.43?(d,?1H),?6.73?(dd,?1H),?7.03?(dt,?1H),?7.14?(d,?1H),?7.20?(d,?1H),?7.39-7.44?(m,?2H),?7.91?(dd,?1H),?8.00?(d,?1H),?8.05?(d,?1H),?8.87?(d,?1H),?8.89?(d,?1H)?9.10?(sbr,?1H)。
Embodiment 55A
1-(2-ethoxyl phenenyl)-3-methyl isophthalic acid H-pyrazoles-5-amine
2.000 gram (10.601 mmole) 2-ethoxyl phenenyl hydrazonium salt hydrochlorates are placed 10 milliliters of 1N hydrochloric acid and add the amino propenyl cyanide of 0.923 gram (11.237 mmole) 3-.This mixture was stirred 18 hours down at 100 ℃.After cooling, the pH value of this mixture is adjusted to pH with the 1N sodium hydroxide solution〉12.It is used dichloromethane extraction three times.The organic phase that merges is washed with saturated sodium-chloride water solution, through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.Product is dry under high vacuum.We obtain the target compound of 2.100 grams (according to the purity 91% of LC-MS, theoretical value 83%).
LC-MS (method 3): R
t=0.57 min; MS (EIpos): m/z=218 [M+H]
+
Embodiment 56A
Methyl-5-methoxyl group-2-{[1-(2-ethoxyl phenenyl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino } benzoic ether
Under argon atmospher, with 2.000 grams (about 8.377 mmoles) from the compound dissolution of embodiment 55A in 16 milliliters of toluene and add 1.711 gram (6.980 mmole) methyl-2-bromo-5-methoxybenzoic acid esters, 2.075 gram (9.773 mmole) potassiumphosphates, 0.281 gram (0.942 mmole) (2-xenyl) two-
The tertiary butylPhosphine and 0.141 gram (0.628 mmole) acid chloride (II).This mixture seethes with excitement whole night under refluxing.After cooling, it uses ethyl acetate extraction.The organic phase that merges washes with water, through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain 1.323 milligrams (theoretical values 41%).
LC-MS (method 4): R
t=1.34 min; MS (EIpos): m/z=382 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?1.20?(t,?3H),?2.21?(s,?3H),?3.70?(s,?3H),?3.79?(s,?3H),?4.10?(q,?2H),?6.09?(s,?1H),?7.03?(dt,?1H),?7.11?(dd,?1H),?7.17-7.21?(m,?2H),?7.30?(d,?1H),?7.33?(dd,?1H),?7.38-7.42?(m,?1H),?9.13?(sbr,?1H)。
Embodiment 57A
Methyl-2-{[4-bromo-1-(2-ethoxyl phenenyl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino }-5-anisole carboxylicesters
With 1280 milligrams (3.356 mmoles) from the compound dissolution of embodiment 56A in 18 milliliters of methylene dichloride, and under 0-5 ℃, add 478 milligrams of (1.678 mmoles) 1,3-two bromo-5,5-T10.Stir after 20 minutes, make it be warming up to room temperature.Add methylene dichloride and with organic phase with twice of 10% sodium thiosulfate solution and saturated sodium-chloride water solution and water washing.Organic phase through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.We obtain the target compound of 1423 milligrams (theoretical values 92%).
LC-MS (method 4): R
t=1.48 min; MS (EIpos): m/z=460 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?1.30?(t,?3H),?2.24?(s,?3H),?3.67?(s,?3H),?3.83?(s,?3H),?4.10?(q,?2H),?6.50?(d,?1H),?7.00?(dt,?1H),?7.05?(dd,?1H),?7.17?(d,?1H),?7.26?(d,?1H),?7.35?(dd,?1H),?7.37-7.41?(m,?1H),?8.87?(sbr,?1H)。
Embodiment 58A
Methyl-2-{[4-(quinoxalin-6-yl)-1-(2-ethoxyl phenenyl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino }-5-methoxybenzoic acid ester
Under argon atmospher, with 350 milligrams (0.760 mmoles) from the compound dissolution of embodiment 57A in 8 milliliters of dimethyl formamides and add 481 milligrams of (2.285 mmole) quinoxalin-6-yl borate hydrochlorates and 1.9 milliliters of 2N aqueous sodium carbonates.Adding 53 milligrams of (0.046 mmoles) four (triphenyl phosphine) palladiums (0) also heats this mixture 45 minutes down at 110 ℃.After cooling, it uses ethyl acetate extraction.The organic phase that merges washes with water, through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 215 milligrams (theoretical values 55%).
LC-MS (method 4): R
t=1.32 min; MS (EIpos): m/z=510 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?1.37?(t,?3H),?2.47?(s,?3H),?3.52?(s,?3H),?3.84?(s,?3H),?4.16?(q,?2H),?6.42?(d,?1H),?6.71?(dd,?1H),?7.02?(dt,?1H),?7.13?(d,?1H),?7.20?(d,?1H),?7.37-7.43?(m,?2H),?7.90?(dd,?1H),?8.01?(d,?1H),?8.03?(d,?1H),?8.87?(d,?1H),?8.89?(d,?1H)?9.13?(sbr,?1H)。
Embodiment 59A
Methyl-2-bromo-5-hydroxybenzene carboxylicesters
5.00 gram (20.4 mmole) methyl-2-bromo-5-anisole carboxylicesterss are dissolved in 95 milliliters of methylene dichloride and are cooled to-78 ℃.Dropwise add 61.0 milliliters of (61.0 mmole) boron tribromides lentamente with the 1N solution form in methylene dichloride subsequently.Be heated to room temperature and stirred overnight subsequently.Then carefully and under ice-cooled situation it is decomposed with methanol solvate.This reaction soln is concentrated in rotatory evaporator, be dissolved in and also use dichloromethane extraction (2x) in the water subsequently.The organic phase that merges is through dried over mgso, and removes by underpressure distillation and to desolvate.Crude product is by MPLC purification (Puriflash Analogix:40M: isohexane/ethyl acetate=4/1).We obtain the target compound of 3.19 grams (theoretical value 68%).
LC-MS (method 4): R
t=0.93 min; MS (EIpos): m/z=231 [M]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?3.83?(s,?3H),?6.88?(dd,?1H),?7.14?(d,?1H),?7.50?(d,?1H),?10.09?(s,?1H)。
Embodiment 60A
Methyl-2-bromo-5-(difluoro-methoxy) benzene carboxylic acid ester
With 1.00 grams (4.33 mmole) from the compound dissolution of embodiment 59A in 60 milliliters of dimethyl formamides.Add 1.65 gram (10.8 mmole) difluoro sodium chloroacetate and 164 milligrams of (4.11 mmole) sodium hydroxide subsequently.It was also stirred 24 hours down at 120 ℃ 100 ℃ of following stirred overnight again.This reaction mixture concentrates in rotatory evaporator and residue is dissolved in the water.Subsequently it is used ethyl acetate extraction (3x).The organic phase that merges is with after dried over mgso and remove by underpressure distillation and to desolvate.Crude product is by MPLC purification (Puriflash Analogix:40M: isohexane/ethyl acetate=95/5).We obtain the target compound of 105 milligrams (theoretical values 9%).
LC-MS (method 4): R
t=1.21 min; MS (EIpos): m/z=281 [M]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?3.87?(s,?3H),?7.31?(t,?1H),?7.33?(dd,?1H),?7.57?(d,?1H),?7.81?(d,?1H)。
Embodiment 61A
Methyl-2-{[4-(quinoxalin-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-5-(difluoro-methoxy) benzene carboxylic acid ester
With 227 milligrams (0.534 mmoles) from the compound dissolution of embodiment 1A in 5 milliliters of toluene.It uses the argon gas rinsing subsequently, and adds 4.0 milligrams of (0.018 mmole) acid chlorides (II) and 19.2 milligrams (0.036 mmole) two (2-diphenylphosphino phenyl) ether.It was at room temperature stirred 5 minutes.Form brown solution.Add 100 milligrams (0.356 mmoles) subsequently from compound and 163 milligrams of (0.498 mmole) cesium carbonates of embodiment 60A and make this mixture reaction is whole night down at 95 ℃.This reaction mixture filters on diatomite.It washs with ethyl acetate again.Remove by underpressure distillation and to desolvate.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 70 milligrams (theoretical values 38%).
LC-MS (method 10): R
t=1.21 min; MS (EIpos): m/z=516 [M]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.18?(s,?3H),?2.48?(s,?3H),?3.82?(s,?3H),?6.51?(d,?1H),?6.95?(t,?1H),?7.05?(dd,?1H),?7.25?(m,?1H),?7.30-7.34?(m,?2H),?7.40?(d,?1H),?7.44?(d,?1H),?7.99?(dd,?1H),?8.05?(d,?1H),?8.13?(d,?1H),?8.89?(d,?1H),?8.90?(d,?1H),?9.16?(s,?1H)。
Embodiment 62A
2,3-two fluoro-6-N-methyl-p-nitroanilines
Make each 2.00 gram (11.3 mmole) 1,2,10 batches of 3-three fluoro-4-oil of mirbane and 4.2 milliliters of (29.6 mmole) 7N methanolic ammonia solutions were reacted under 70 ℃ 90 minutes in the single mode microwave in succession.Merge gained solution and in rotatory evaporator, remove volatile constituent.Residue is dissolved in ethyl acetate, washes with water and through dried over sodium sulfate.Remove by underpressure distillation and to desolvate and make residue recrystallization from methanol (1:1).We obtain 14.4 gram target compounds (73% of theoretical value, based on used 1,2, the total amount of 3-three fluoro-4-oil of mirbane).
GC-MS (method 6): R
t=4.09 min; MS (EIpos): m/z=174 [M]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?6.72?(m,?1H),?7.54?(sbr,?2H),?7.93?(m,?1H)。
Embodiment 63A
3-amino-2-fluoro-4-nitrophenol
Restrain 6.44 gram (114.9 mmole) potassium hydroxide that (28.7 mmole) embodiment 62A are dissolved in 50 milliliters of dioxanes and are added in the solution form in 20 ml waters with 5.00.Subsequently with its stirred overnight under reflux temperature.Reaction mixture is added in 80 milliliters of 1M citric acid solutions.Gained solution extracts with ethyl acetate (2x100 milliliter).Organic phase water that merges and saturated sodium-chloride water solution washing and through dried over mgso.Remove desolvate and residue by MPLC (the Puriflash Analogix:40M: isohexane/ethyl acetate=3/1) that purifies.We obtain the target compound of 2.60 grams (theoretical value 49%).
LC-MS (method 10): R
t=0.62 min; MS (EIneg): m/z=172 [M-H]
-
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?6.30?(dd,?1H),?7.19?(sbr,?2H),?7.75?(dd,?1H),?11.09?(s,?1H)。
Embodiment 64A
2-fluoro-3-methoxyl group-6-N-methyl-p-nitroaniline
1.70 gram (9.88 mmole) embodiment 63A are dissolved in 20 milliliters of tetrahydrofuran (THF)s and add 0.40 milliliter of (9.88 mmole) methyl alcohol.After adding 2.85 gram (10.9 mmole) triphenyl phosphines, with it in cooling on the ice bath and in 5 minutes, dropwise add 2.10 milliliters of (10.9 mmole) diisopropyl azo-2-carboxylic acids.This reaction mixture was at room temperature stirred 2.5 hours.With this mixture evaporation concentration and by column chromatography purification (silica gel: cyclohexane/ethyl acetate=3/1).We obtain the target compound of 3.50 grams (theoretical value 95%), 50% purity (LC-MS).Find that pollutent is a di-isopropyl hydrazine-1, the 2-dicarboxylic ester.Thus obtained material is used without further purification.
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?3.92?(s,?3H),?6.61?(dd,?1H),?7.14?(sbr,?2H),?7.90?(dd,?1H)。
Embodiment 65A
4-bromo-2-fluoro-3-methoxyl group-6-N-methyl-p-nitroaniline
1.80 gram (about 4.83 mmoles) embodiment 64A are dissolved in 25 milliliters of acetate and add 946 milligrams of (5.32 mmole) N-bromosuccinimides.It was stirred 4 hours under reflux temperature.Subsequently it is added in 100 ml waters and the filtering separation precipitated solid.This solid washes with water and is dry under high vacuum subsequently.We obtain the target compound of 1.08 grams (theoretical value 84%).
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?4.04?(d,?3H),?7.49?(sbr,?2H),?8.05?(d,?1H)。
Embodiment 66A
5-bromo-3-fluoro-4-anisole-1, the 2-diamines
1.08 gram (4.15 mmole) embodiment 65A are dissolved in 50 milliliters of ethanol and 10 ml waters and are heated to 80 ℃.Be added in 2.89 gram (16.6 mmole) V-Brite Bs of the solution form in 15 ml waters subsequently., add 1.08 gram (6.22 mmole) V-Brite Bs again and under uniform temp, continue reaction 45 minutes after 60 minutes in reaction under 80 ℃.With this mixture evaporation concentration to possible at utmost and leach the gained throw out.It is washed with water and drying under high vacuum.We obtain the target compound of 600 milligrams (theoretical values 62%).
LC-MS (method 10): R
t=0.72 min; MS (EIpos): m/z=235 [M]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?3.67?(s,?3H),?4.64?(sbr,?2H),?4.80?(sbr,?2H),?6.50?(d,?1H)。
Embodiment 67A
7-bromo-5-fluoro-6-methoxyl group quinoxaline
600 milligrams of (2.55 mmole) embodiment 66A are dissolved in 25 milliliters of ethanol, add 307 milligrams of (2.55 mmoles) 1,4-dioxane-2,3-glycol and its stirred overnight at room temperature.Be dissolved in 50 milliliters of methylene dichloride with this mixture evaporation concentration and with residue.Organic phase water and saturated sodium-chloride water solution washing.Subsequently it is removed through dried over mgso and in rotatory evaporator and desolvate.This residue is dry under high vacuum at last.We obtain the target compound of 377 milligrams (theoretical values 57%).
LC-MS (method 10): R
t=0.90 min; MS (EIpos): m/z=258 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?4.12?(s,?3H),?8.32?(d,?1H),?8.97?(d,?1H),?9.01?(d,?1H)。
Embodiment 68A
Methyl-2-{[3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } the benzene carboxylic acid ester
Under argon atmospher, 6.53 gram (34.9 mmole) 3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-amine (be described in WO 2004/050650, the 30 page in) are dissolved in 100 milliliters of pure toluenes.It is used argon purge, and add 261 milligrams of (1.16 mmole) acid chlorides (II) and 1.25 gram (2.33 mmole) two (2-diphenylphosphino phenyl) ethers (DPEphos).Subsequently it was at room temperature stirred 5 minutes.Add 5.00 gram (23.3 mmole) methyl-2-bromo-benzoates and 5.00 gram (23.3 mmole) cesium carbonates subsequently also subsequently 95 ℃ of following stirred overnight.With reaction mixture cooling and on diatomite, filter.It washs with ethyl acetate again.Subsequently the organic phase that merges is concentrated in rotatory evaporator, and residue is by column chromatography purification (silica gel: cyclohexane/ethyl acetate=7/3).We obtain the target compound of 7.37 grams (theoretical value 98%).
LC-MS (method 4): R
t=1.34 min; MS (EIpos): m/z=322 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.03?(s,?3H),?2.24?(s,?3H),?3.72?(s,?3H),?6.21?(s,?1H),?6.83?(t,?1H),?7.24?(d,?1H),?7.29-7.34?(m,?2H),?7.36-7.41?(m,?2H),?7.49?(mc,?1H),?7.83?(dd,?1H),?9.27?(s,?1H)。
Embodiment 69A
Methyl-2-{[4-bromo-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } the benzene carboxylic acid ester
With 7.35 grams (22.9 mmole) from the compound dissolution of embodiment 68A in 150 milliliters of methylene dichloride, and, add 3.27 and restrain (11.5 mmoles) 1,3-two bromo-5,5-T10 with in ice-cooled.After reaction 10 minutes, it dilutes with 150 milliliters of methylene dichloride and washs with each 150 ml water, saturated sodium bicarbonate aqueous solution with 10% sodium thiosulfate solution.Subsequently it is removed through dried over mgso and in rotatory evaporator and desolvate.We obtain the target compound of 8.28 grams (theoretical value 90%).
LC-MS (method 10): R
t=1.33 min; MS (EIpos): m/z=400 [M]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.09?(s,?3H),?2.27?(s,?3H),?3.80?(s,?3H),?6.55?(d,?1H),?6.79?(t,?1H),?7.23?(m,?1H),?7.28-7.36?(m,?3H),?7.39?(t,?1H),?7.79?(dd,?1H),?8.99?(s,?1H)。
Embodiment 70A
Methyl-2-{[4-(8-fluoro-7-methoxyl group quinoxalin-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } the benzene carboxylic acid ester
Stage 1
Under argon atmospher, 375 milligrams of (1.46 mmole) embodiment 67A are dissolved in 15 milliliters of dioxanes.Add 258 milligrams of (2.63 mmole) potassium acetates, 95 milligrams of (0.12 mmoles) 1 subsequently, 1'-pair-(diphenylphosphino) ferrocene Palladous chloride (II)-methylene dichloride complex compound and 407 milligrams of (1.61 mmoles) 4,4,4'4'5,5,5'5'-prestox-2,2'-two-1,3,2-two oxa-borines.With reaction mixture stirred overnight under 130 ℃ of oil bath temperatures.After cooling, dioxane added in the reaction mixture and with it on diatomite, filter.It washs with ethyl acetate again.Filtrate is concentrating under reduced pressure and dry under high vacuum in rotatory evaporator.We obtain 610 milligrams of 5-fluoro-6-methoxyl group-7-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl) quinoxaline as crude product.Make its reaction without further purifying subsequently.
Stage 2
Under argon atmospher, with 209 milligrams of thus obtained 5-fluoro-6-methoxyl group-7-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl) the quinoxaline crude product is dissolved in 5 milliliters of dioxanes with 300 milligrams of (0.813 mmole) embodiment 69A, 25 milligrams of (0.090 mmole) tricyclohexyl phosphines, 34 milligrams of (0.037 mmole) three (dibenzylidene-acetone)-two palladiums and 1.27 milliliters of (1.27 mmole) 1M potassium phosphate solutions.It is reacted whole night down at 100 ℃.After cooling, this mixture filters on diatomite, washs and remove volatile constituent with ethyl acetate in rotatory evaporator again.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 161 milligrams (theoretical values 43%), about 50% purity (LC-MS).Determine that pollutent is methyl-2-{[3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } the benzene carboxylic acid ester.Thus obtained material uses without further handling promptly subsequently.
LC-MS (method 10): R
t=1.23 min; MS (EIpos): m/z=498 [M+H]
+
Embodiment 71A
Methyl-2-[(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl) amino] the benzene carboxylic acid ester
Under argon atmospher, be dissolved in 8.00 gram (46.184 mmole) 5-amino-3-methyl isophthalic acid-phenylpyrazoles in 130 milliliters of toluene and add 0.346 gram (1.539 mmole) acid chloride (II) and 1.658 restrain (3.079 mmole) two-[2-diphenylphosphino)-phenyl]-ether.This mixture was at room temperature stirred 5 minutes.Add subsequently 6.621 the gram (30.789 mmole) methyl-2-bromo-benzoates and 14.045 the gram (43.105 mmole) cesium carbonates and with this mixture 95 ℃ of following stirred overnight.After cooling, it is filtered on silica gel, with this suction filter filter cake with ethyl acetate washing and with the filtrate evaporation concentration.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 20:80 → 90:10).We obtain the target compound of 9.36 grams (theoretical value 66%).
LC-MS (method 10): R
t=1.18 min; MS (EIpos): m/z=308 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.25?(s,?3H),?3.80?(s,?3H),?6.23?(s,?1H),?6.82?(t,?1H),?6.94?(d,?1H),?7.33?(t,?1H),?7.37-7.49?(m,?3H),?7.49-7.58?(m,?2H),?7.86?(d,?1H),?9.38?(s,?1H)。
Embodiment 72A
Methyl-2-[(4-bromo-3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl) amino] the benzene carboxylic acid ester
With 9.370 grams (30.486 mmole) from the compound dissolution of embodiment 71A in 160 milliliters of methylene dichloride, and with in ice-cooled, portioning adds 4.358 and restrains (15.243 mmoles) 1,3-two bromo-5,5-T10.Reaction test by HPLC shows to be finished after being reflected at 20 minutes.Add methylene dichloride and organic phase water, saturated sodium bicarbonate aqueous solution and the washing of 10% sodium thiosulfate solution.Organic phase is with after dried over sodium sulfate and concentrating in rotatory evaporator.We obtain the target compound of 11.441 grams (theoretical value 96%).
LC-MS (method 10): R
t=1.32 min; MS (EIpos): m/z=386 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.28?(s,?3H),?3.86?(s,?3H),?6.36?(d,?1H),?6.79?(t,?1H),?7.26-7.37?(m,?2H),?7.37-7.46?(m,?2H),?7.50-7.60?(m,?2H),?7.84?(d,?1H),?9.14?(s,?1H)。
Embodiment 73A
Methyl-2-{[4-(8-fluoro-7-methoxyl group quinoxalin-6-yl)-3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl] amino } the benzene carboxylic acid ester
Under argon atmospher, with 215 milligrams of 5-fluoro-6-methoxyl group-7-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl) quinoxaline (crude product is referring to the embodiment 70A stage 1) is dissolved in 5 milliliters of dioxanes with 300 milligrams of (0.777 mmole) embodiment 72A, 26 milligrams of (0.093 mmole) tricyclohexyl phosphines, 36 milligrams of (0.039 mmole) three (dibenzylidene-acetone)-two palladiums and 1.32 milliliters of (1.32 mmole) 1M potassium phosphate solutions.It is reacted whole night down at 100 ℃.After cooling, this mixture filters on diatomite, washs and remove volatile constituent with ethyl acetate in rotatory evaporator again.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 162 milligrams (theoretical values 43%), about 60% purity (LC-MS).Determine that pollutent is methyl-2-{[3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } the benzene carboxylic acid ester.Thus obtained material uses without further handling promptly subsequently.
LC-MS (method 10): R
t=1.23 min; MS (EIpos): m/z=483 [M+H]
+
Embodiment 74A
7-bromo-2-methoxyl group quinoxaline
With 600 milligrams of (2.67 mmole) 7-bromine quinoxalines-2 (1H)-ketone [people such as Lumma,
J. Med. Chem.1981,24,93] and 1.73 milliliters of (3.47 mmole) trimethyl silyl diazomethanes be dissolved in 5.25 ml methanol/acetonitrile/methylene dichloride (1/10/10).Add 0.483 milliliter of (3.47 mmole) triethylamine subsequently and with its stirred overnight at room temperature.With this mixture evaporation concentration and residue by MPLC (the Puriflash Analogix:40M: isohexane/ethyl acetate=9/1 → isohexane/ethyl acetate=3/1) that purifies.We obtain the target compound of 140 milligrams (theoretical values 22%).
LC-MS (method 10): R
t=1.09 min; MS (EIpos): m/z=240 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?4.04?(s,?3H),?7.78?(dd,?1H),?7.96?(d,?1H),?8.06?(d,?1H),?8.64?(s,?1H)。
Embodiment 75A
Methyl-2-{[4-(3-methoxyl group quinoxalin-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } the benzene carboxylic acid ester
Stage 1
Under argon atmospher, 140 milligrams of (0.586 mmole) embodiment 74A are dissolved in 15 milliliters of dioxanes.Add 172 milligrams of (1.76 mmole) potassium acetates, 38 milligrams of (0.047 mmoles) 1 subsequently, 1'-pair-(diphenylphosphino) ferrocene Palladous chloride (II)-methylene dichloride complex compound and 163 milligrams of (0.644 mmoles) 4,4,4'4'5,5,5'5'-prestox-2,2'-two-1,3,2-two oxa-borines.With reaction mixture stirred overnight under 130 ℃ of oil bath temperatures.After cooling, dioxane added in the reaction mixture and with it on diatomite, filter.It washs with ethyl acetate again.Filtrate is concentrating under reduced pressure and dry under high vacuum in rotatory evaporator.We obtain 152 milligrams of 2-methoxyl group-7-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl) quinoxaline as crude product.Even subsequently without its reaction of further purifying.
Stage 2
Under argon atmospher, with 150 milligrams of thus obtained 2-methoxyl group-7-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl) the quinoxaline crude product is dissolved in 10 milliliters of dioxanes with 142 milligrams of (0.356 mmole) embodiment 69A, 12 milligrams of (0.043 mmole) tricyclohexyl phosphines, 16 milligrams of (0.018 mmole) three (dibenzylidene-acetone)-two palladiums and 0.61 milliliter of (0.61 mmole) 1M potassium phosphate solution.It is reacted whole night down at 100 ℃.After cooling, this mixture filters on diatomite, washs and remove volatile constituent with ethyl acetate in rotatory evaporator again.With this mixture evaporation concentration and residue by MPLC (the Puriflash Analogix:40S: isohexane/ethyl acetate=95/5 → isohexane/ethyl acetate=10/90) that purifies.We obtain the target compound of 30 milligrams (theoretical values about 14%), about 80% purity (LC-MS).Thus obtained material uses without further handling promptly subsequently.
LC-MS (method 10): R
t=1.34 min; MS (EIpos): m/z=480 [M+H]
+
Embodiment 76A
Methyl-2-{[4-(quinoline-7-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } the benzene carboxylic acid ester
Stage 1
Under argon atmospher, with 600 milligrams of (2.884 mmole) 7-bromoquinolines [people such as Butler,
J. Heterocycl. Chem.1975,12,1015] be dissolved in 25 milliliters of dioxanes.Add 509 milligrams of (5.19 mmole) potassium acetates, 188 milligrams of (0.231 mmoles) 1 subsequently, 1'-pair-(diphenylphosphino) ferrocene Palladous chloride (II)-methylene dichloride complex compound and 805 milligrams of (3.17 mmoles) 4,4,4'4'5,5,5'5'-prestox-2,2'-two-1,3,2-two oxa-borines.With reaction mixture stirred overnight under 130 ℃ of oil bath temperatures.After cooling, dioxane added in the reaction mixture and with it on diatomite, filter.It washs with ethyl acetate again.Filtrate is concentrating under reduced pressure and dry under high vacuum in rotatory evaporator.We obtain 1100 milligrams of 7-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl) quinoline as crude product.Even subsequently without its reaction of further purifying.
Stage 2
Under argon atmospher, with 202 milligrams of thus obtained 7-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl) the quinoline crude product is dissolved in 5 milliliters of dioxanes with 150 milligrams of (0.468 mmole) embodiment 69A, 13 milligrams of (0.045 mmole) tricyclohexyl phosphines, 19 milligrams of (0.019 mmole) three (dibenzylidene-acetone)-two palladiums and 0.637 milliliter of (0.637 mmole) 1M potassium phosphate solution.It is reacted whole night down at 100 ℃.The filtering separation solids component, in rotatory evaporator, remove desolvate and with reaction mixture by HPLC (the Puriflash Analogix:40S: isohexane/ethyl acetate=95/5 → isohexane/ethyl acetate=10/90) that purifies.We obtain the target compound of 37 milligrams (theoretical values 22%).
LC-MS (method 4): R
t=1.27 min; MS (EIpos): m/z=449 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.18?(s,?3H),?2.47?(s,?3H),?3.79?(s,?3H),?6.48?(d,?1H),?6.59?(t,?1H),?7.16?(t,?1H),?7.23?(m,?1H),?7.27-7.36?(m,?2H),?7.43?(d,?1H),?7.47?(dd,?1H),?7.65?(dd,?1H),?7.71?(dd,?1H),?7.92?(d,?1H),?8.04?(s,?1H),?8.29?(d,?1H),?8.85?(d,?1H),?9.21?(s,?1H)。
Embodiment 77A
7-bromo-N, N-dimethyl quinoxaline-2-amine
Make 500 milligrams of (2.053 mmole) 2-chloro-7-bromoquinolines [people such as Wolf,
J. Am. Chem. Soc.,1949,71,6] and 5.13 milliliters of (10.27 mmole) dimethyl amines in the single mode microwave 120 ℃ of reactions 8 hours down.In rotatory evaporator, remove volatile constituent and residue subsequently by HPLC purification (Puriflash Analogix:40S: isohexane/ethyl acetate=95/5 → isohexane/ethyl acetate=10/90).We obtain the target compound of 230 milligrams (theoretical values 44%).
LC-MS (method 10): R
t=1.05 min; MS (EIpos): m/z=252 [M]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?3.23?(s,?6H),?7.47?(dd,?1H),?7.70-7.79?(m,?2H),?8.71?(s,?1H)。
Embodiment 78A
Methyl-2-(4-[3-(dimethylamino) quinoxalin-6-yl]-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl } amino) the benzene carboxylic acid ester
Stage 1
Under argon atmospher, 230 milligrams of (0.912 mmole) embodiment 77A are dissolved in 10 milliliters of dioxanes.Add 269 milligrams of (2.74 mmole) potassium acetates, 59 milligrams of (0.073 mmoles) 1 subsequently, 1'-pair-(diphenylphosphino) ferrocene Palladous chloride (II)-methylene dichloride complex compound and 255 milligrams of (1.003 mmoles) 4,4,4'4'5,5,5'5'-prestox-2,2'-two-1,3,2-two oxa-borines.With reaction mixture stirred overnight under 130 ℃ of oil bath temperatures.After cooling, methylene dichloride added in the reaction mixture and with it on diatomite, filter.It washs with ethyl acetate again.Filtrate is concentrating under reduced pressure and dry under high vacuum in rotatory evaporator.We obtain 280 milligrams of N, and N-dimethyl-7-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl) quinoxalines-2-amine [42%, also contain 45% corresponding boric acid (LC-MS)] are as crude product.Even subsequently without its reaction of further purifying.
Stage 2
Under argon atmospher, with 272 milligrams of thus obtained N, N-dimethyl-7-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl) quinoxaline-2-amine crude product is dissolved in 17 milliliters of dioxanes with 242 milligrams of (0.606 mmole) embodiment 69A, 20 milligrams of (0.073 mmole) tricyclohexyl phosphines, 28 milligrams of (0.030 mmole) three (dibenzylidene-acetone)-two palladiums and 1.03 milliliters of (1.03 mmole) 1M potassium phosphate solutions.It is reacted whole night down at 100 ℃.After cooling, this mixture filters on diatomite, washs and remove volatile constituent with ethyl acetate in rotatory evaporator again.With this mixture evaporation concentration and residue by MPLC (the Puriflash Analogix:40S: isohexane/ethyl acetate=95/5 → isohexane/ethyl acetate=10/90) that purifies.We obtain the target compound of 79 milligrams (theoretical values 26%).
LC-MS (method 10): R
t=1.27 min; MS (EIpos): m/z=493 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.17?(s,?3H),?2.41?(s,?3H),?3.20?(s,?6H),?3.79?(s,?3H),?6.46?(d,?1H),?6.59?(t,?1H),?7.15?(t,?1H),?7.23?(mc,?1H),?7.27-7.35?(m,?2H),?7.41?(t,?2H),?7.60-7.67?(m,?2H),?7.71?(d,?1H),?8.61?(s,?1H),?9.17?(s,?1H)。
Embodiment 79A
3-amino-6-bromo-2-fluoro-4-nitrophenol
With 2.60 the gram (15.1 mmole) embodiment 63A be dissolved in 80 milliliters of acetate and add 2.96 the gram (16.6 mmole) N-bromosuccinimides.Subsequently it was stirred 4 hours under reflux temperature.Remove and desolvate, and residue is by column chromatography purification (silica gel: cyclohexane/ethyl acetate=1/1).We obtain the target compound of 2.10 grams (theoretical value 46%).
LC-MS (method 10): R
t=0.81 min; MS (EIpos): m/z=251 [M]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?7.34?(sbr,?2H),?8.01?(d,?1H),?11.84?(sbr,?1H)。
Embodiment 80A
3,4-diamino-6-bromo-2-fluorophenol
With 2.10 the gram (8.37 mmole) embodiment 79A be dissolved in 50 milliliters of ethanol and add 7.56 the gram (33.5 mmole) two hydration tin chlorides (II).Subsequently with it 70 ℃ of following stirred overnight.Be dissolved in 100 ml waters with this mixture evaporation concentration and with residue.Make it be weakly alkaline with saturated sodium bicarbonate aqueous solution subsequently and add 100 milliliters of ethyl acetate.It is filtered on diatomite and filter cake washs with ethyl acetate again.Separate organic phase and water ethyl acetate extraction (2x).The organic phase that merges is dry and remove in rotatory evaporator and desolvate.Thus, we obtain the target compound of 1.10 grams (theoretical value 58%), purity 97%(LC-MS).
LC-MS (method 4): R
t=0.26 min; MS (EIpos): m/z=221 [M]
+
Embodiment 81A
7-bromo-5-fluorine quinoxaline-6-alcohol
1.10 gram (4.98 mmole) embodiment 80A are dissolved in 40 milliliters of ethanol and add 598 milligrams of (4.98 mmoles) 1,4-dioxane-2,3-glycol.Subsequently with its stirred overnight at room temperature.Remove volatile constituent and residue is dissolved in the methylene dichloride.With its water and saturated sodium-chloride water solution washing.Subsequently with it through dried over mgso.With this mixture evaporation concentration and residue by MPLC (the Puriflash Analogix:40M: isohexane/ethyl acetate=1/1) that purifies.We obtain the target compound of 603 milligrams (theoretical values 49%).
LC-MS (method 10): R
t=0.68 min; MS (EIpos): m/z=243 [M]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?8.24?(d,?1H),?8.85?(d,?1H),?8.93?(d,?1H),?11.61?(s,?1H)。
Embodiment 82A
Methyl-2-{[4-(8-fluoro-7-hydroxy quinoxaline-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } the benzene carboxylic acid ester
Stage 1
Under argon atmospher, 230 milligrams of (0.946 mmole) embodiment 81A are dissolved in 10 milliliters of dioxanes.Add 168 milligrams of (1.70 mmole) potassium acetates, 62 milligrams of (0.076 mmoles) 1 subsequently, 1'-pair-(diphenylphosphino) ferrocene Palladous chloride (II)-methylene dichloride complex compound and 264 milligrams of (1.04 mmoles) 4,4,4'4'5,5,5'5'-prestox-2,2'-two-1,3,2-two oxa-borines.With reaction mixture stirred overnight under 130 ℃ of oil bath temperatures.After cooling, dioxane added in the reaction mixture and with it on diatomite, filter.It washs with ethyl acetate again.Filtrate is concentrating under reduced pressure and dry under high vacuum in rotatory evaporator.We obtain 474 milligrams of 8-fluoro-7-hydroxy quinoxaline-6-yls) boric acid is as crude product, 32% purity (LC-MS).Even subsequently without its reaction of further purifying.
Stage 2
Under argon atmospher, with 202 milligrams of thus obtained 8-fluoro-7-hydroxy quinoxaline-6-yls) the boric acid crude product is dissolved in 5 milliliters of dioxanes with 100 milligrams of (0.813 mmole) embodiment 69A, 8.4 milligrams of (0.030 mmole) tricyclohexyl phosphines, 11.4 milligrams of (0.012 mmole) three (dibenzylidene-acetone)-two palladiums and 0.425 milliliter of (0.425 mmole) 1M potassium phosphate solution.It is reacted whole night down at 100 ℃.After cooling, this mixture filters on diatomite, washs and remove volatile constituent with ethyl acetate in rotatory evaporator again.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 5 milligrams (theoretical values 4%).
LC-MS (method 10): R
t=1.05 min; MS (EIpos): m/z=484 [M+H]
+
Embodiment 83A
7-bromo-6-oxyethyl group-5-fluorine quinoxaline
Be dissolved in 150 milligrams of (0.617 mmole) embodiment 81A in 5 milliliters of tetrahydrofuran (THF)s and add 0.036 milliliter of (0.617 mmole) ethanol.After adding 178 milligrams of (0.679 mmole) triphenyl phosphines, with it in cooling on the ice bath and in 5 minutes, dropwise add 0.131 milliliter of (0.679 mmole) diisopropyl azo-2-carboxylic acid.This reaction mixture slowly is heated to room temperature and restir 30 minutes at ambient temperature subsequently.In rotatory evaporator, remove volatile constituent and residue subsequently by the preparation HPLC (eluent: acetonitrile/water, gradient 10:90 → 90:10) of purifying.We obtain the target compound of 100 milligrams (theoretical values 60%).
LC-MS (method 2): R
t=2.07 min; MS (EIpos): m/z=271 [M]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?1.43?(t,?3H),?4.37?(q,?2H),?8.32?(d,?1H),?8.98?(d,?1H),?9.01?(d,?1H)。
Embodiment 84A
Methyl-2-{[4-(7-oxyethyl group-8-fluorine quinoxalin-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } the benzene carboxylic acid ester
Stage 1
Under argon atmospher, 100 milligrams of (0.369 mmole) embodiment 83A are dissolved in 4 milliliters of dioxanes.Add 65.1 milligrams of (0.664 mmole) potassium acetates, 24.1 milligrams of (0.030 mmoles) 1 subsequently, 1'-pair-(diphenylphosphino) ferrocene Palladous chloride (II)-methylene dichloride complex compound and 103 milligrams of (0.406 mmoles) 4,4,4'4'5,5,5'5'-prestox-2,2'-two-1,3,2-two oxa-borines.With reaction mixture stirred overnight under 130 ℃ of oil bath temperatures.After cooling, methylene dichloride added in the reaction mixture and with it on diatomite, filter.It washs with ethyl acetate again.Filtrate is concentrating under reduced pressure and dry under high vacuum in rotatory evaporator.We obtain 200 milligrams of 6-oxyethyl groups-5-fluoro-7-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl) quinoxaline [87%, (LC-MS)] as crude product.Even subsequently without its reaction of further purifying.
Stage 2
Under argon atmospher, with 100 milligrams of thus obtained 6-oxyethyl group-5-fluoro-7-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl) the quinoxaline crude product is dissolved in 4 milliliters of dioxanes with 73 milligrams of (0.312 mmole) embodiment 69A, 8.4 milligrams of (0.030 mmole) tricyclohexyl phosphines, 11.4 milligrams of (0.012 mmole) three (dibenzylidene-acetone)-two palladiums and 0.425 milliliter of (0.425 mmole) 1M potassium phosphate solution.It is reacted whole night under reflux temperature.In rotatory evaporator, remove volatile constituent and residue subsequently by the preparation HPLC (eluent: acetonitrile/water, gradient 10:90 → 90:10) of purifying.We obtain the target compound of 37 milligrams (theoretical values 28%).
LC-MS (method 10): R
t=1.26 min; MS (EIpos): m/z=512 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?1.30?(t,?3H),?2.21?(s,?3H),?2.31?(s,?3H),?3.78?(s,?3H),?4.20?(q,?2H),?6.48?(d,?1H),?6.56?(t,?1H),?7.12?(t,?1H),?7.16-7.35?(m,?3H),?7.39?(d,?1H),?7.59?(d,?1H),?7.93?(s,?1H),?8.91?(d,?2H),?9.15?(s,?1H)。
Embodiment 85A
2-[(7-bromo-5-fluorine quinoxalin-6-yl) oxygen base] ethylhexoate
Be dissolved in 150 milligrams of (0.617 mmole) embodiment 81A in 5 milliliters of tetrahydrofuran (THF)s and add 0.128 milliliter of (0.617 mmole, 50%) 2-acetoxyl group ethanol.After adding 178 milligrams of (0.679 mmole) triphenyl phosphines, with it in cooling on the ice bath and in 5 minutes, dropwise add 0.131 milliliter of (0.679 mmole) diisopropyl azo-2-carboxylic acid.This reaction mixture slowly is heated to room temperature and restir 30 minutes at room temperature subsequently.In rotatory evaporator, remove volatile constituent and residue subsequently by the preparation HPLC (eluent: acetonitrile/water, gradient 10:90 → 90:10) of purifying.We obtain 230 milligrams of target compounds, 30% purity (LC-MS).Determine that triphenyl phosphine oxide is a pollutent.Thus obtained material promptly reacts without further purification step.
LC-MS (method 10): R
t=0.90 min; MS (EIpos): m/z=329 [M]
+
Embodiment 86A
Methyl-2-{[4-{7-[2-(acetoxyl group) oxyethyl group]-8-fluorine quinoxalin-6-yl }-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } the benzene carboxylic acid ester
Stage 1
Under argon atmospher, 164 milligrams of embodiment 85A are dissolved in 5 milliliters of dioxanes.Add 88.3 milligrams of (0.900 mmole) potassium acetates, 32.7 milligrams of (0.040 mmoles) 1 subsequently, 1'-pair-(diphenylphosphino) ferrocene Palladous chloride (II)-methylene dichloride complex compound and 139 milligrams of (0.550 mmoles) 4,4,4'4'5,5,5'5'-prestox-2,2'-two-1,3,2-two oxa-borines.With this reaction mixture stirred overnight under 110 ℃ of oil bath temperatures.After cooling, methylene dichloride added in the reaction mixture and with it on diatomite, filter.It washs with ethyl acetate again.Filtrate is concentrating under reduced pressure and dry under high vacuum in rotatory evaporator.We obtain 400 milligrams of { 7-[2-(acetoxyl group) oxyethyl group]-8-fluorine quinoxalin-6-yl } boric acid [17%, (LC-MS)] as crude product.Even subsequently without its reaction of further purifying.
Stage 2
Under argon atmospher, 100 milligrams of thus obtained { 7-[2-(acetoxyl group) oxyethyl group]-8-fluorine quinoxalin-6-yl } boric acid crude products are dissolved in 4 milliliters of dioxanes with 73 milligrams of (0.312 mmole) embodiment 69A, 8.4 milligrams of (0.030 mmole) tricyclohexyl phosphines, 11.4 milligrams of (0.012 mmole) three (dibenzylidene-acetone)-two palladiums and 0.425 milliliter of (0.425 mmole) 1M potassium phosphate solution.It is reacted whole night under reflux temperature.In rotatory evaporator, remove volatile constituent and residue subsequently by the preparation HPLC (eluent: acetonitrile/water, gradient 10:90 → 90:10) of purifying.We obtain the target compound of 40 milligrams (23% of theoretical value is with respect to embodiment 69A).
LC-MS (method 1): R
t=2.56 min; MS (EIpos): m/z=570 [M+H]
+
Embodiment 87A
6-bromo-4-methoxy quinoline
With 300 milligrams of (1.24 mmole) 6-bromo-4-chloroquinoline [people such as Lin,
J. Med. Chem.1978,21,268] be dissolved in 4 ml methanol and add the methanol solution (30 weight %) of 1.15 milliliters of (6.19 mmole) sodium methylate.It was reacted 1 hour down at 120 ℃ in the single mode microwave.In rotatory evaporator, remove and desolvate and make residue phase-splitting between water and ethyl acetate.The water ethyl acetate extraction, and with the organic phase that merges through dried over mgso.Remove by underpressure distillation and to desolvate.Thus, we obtain the target compound of 150 milligrams (theoretical values 36%).
LC-MS (method 2): R
t=1.24 min; MS (EIpos): m/z=238 [M]
+
Embodiment 88A
Methyl-2-{[4-(4-methoxy quinoline-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } the benzene carboxylic acid ester
Stage 1
Under argon atmospher, 150 milligrams of embodiment 87A are dissolved in 4 milliliters of dioxanes.Add 111.3 milligrams of (1.134 mmole) potassium acetates, 41.2 milligrams of (0.050 mmoles) 1 subsequently, 1'-pair-(diphenylphosphino)-ferrocene Palladous chloride (II)-methylene dichloride complex compound and 176 milligrams of (0.693 mmoles) 4,4,4'4'5,5,5'5'-prestox-2,2'-two-1,3,2-two oxa-borines.With this reaction mixture stirred overnight under 110 ℃ of oil bath temperatures.After cooling, methylene dichloride added in the reaction mixture and with it on diatomite, filter.It washs with ethyl acetate again.Filtrate is concentrating under reduced pressure and dry under high vacuum in rotatory evaporator.We obtain 227 milligrams of 4-methoxyl group-6-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl) quinoline [47%, (LC-MS)] as crude product.Even subsequently without its reaction of further purifying.
Stage 2
Under argon atmospher, with 134 milligrams of thus obtained 4-methoxyl group-6-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl) the quinoline crude product is dissolved in 4 milliliters of dioxanes with 150 milligrams of (0.375 mmole) embodiment 69A, 12.6 milligrams of (0.045 mmole) tricyclohexyl phosphines, 17.2 milligrams of (0.019 mmole) three (dibenzylidene-acetone)-two palladiums and 0.637 milliliter of (0.637 mmole) 1M potassium phosphate solution.It is reacted whole night under reflux temperature.After filtration, in rotatory evaporator, remove volatile constituent.This residue passes through preparation HPLC subsequently purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 99 milligrams (54% of theoretical value is with respect to embodiment 69A).
LC-MS (method 10): R
t=0.96 min; MS (EIpos): m/z=479 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.18?(s,?3H),?2.44?(s,?3H),?3.80?(s,?3H),?3.97?(s,?3H),?6.46?(d,?1H),?6.59?(t,?1H),?6.97?(d,?1H),?7.15?(mc,?1H),?7.25?(mc,?1H),?7.28-7.35?(m,?2H),?7.44?(d,?1H),?7.67?(dd,?1H),?7.82?(dd,?1H),?7.87?(d,?1H),?8.11?(d,?1H),?8.66?(d,?1H),?9.18?(s,?1H)。
Embodiment 89A
5-bromo-3-fluorobenzene-1, the 2-diamines
5.00 gram (21.275 mmole) 4-bromo-2 fluoro-6-N-methyl-p-nitroanilines are dissolved in 190 milliliters of ethanol, add 19.20 gram (85.100 mmole) two hydration tin chlorides (II) and with it 70 ℃ of following stirred overnight.After cooling, this mixture concentrates in rotatory evaporator, adds entry and makes it be weakly alkaline with saturated sodium bicarbonate aqueous solution.Ethyl acetate extraction three times of this mixture, the organic phase of merging concentrates through dried over sodium sulfate and in rotatory evaporator.This residue is dry under high vacuum.We obtain the target compound of 4.18 grams (theoretical value 92%), and it is without the further reaction of further purifying promptly.
LC-MS (method 3): R
t=1.29 min; MS (EIpos): m/z=205 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?4.52?(sbr,?2H),?5.10?(sbr,?2H),?6.49-6.52?(m,?2H)。
Embodiment 90A
7-bromo-5-fluorine quinoxaline
With 4.00 grams (19.509 mmole) from the compound dissolution of embodiment 89A in 100 milliliters of ethanol and add 2.42 gram (19.509 mmoles) 2,3-dihydroxyl-1,4-dioxane.With this mixture at room temperature stir 4 hours and add again 2.42 the gram (19.509 mmoles) 2,3-dihydroxyl-1,4-dioxane.After at room temperature stirring 24 hours, this mixture concentrated in rotatory evaporator and residue by the silica gel chromatography (eluent: methylene chloride=30:1) of purifying.We obtain the target compound of 3.60 grams (theoretical value 80%).
LC-MS (method 1): R
t=1.79 min; MS (EIpos): m/z=227 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?8.06?(dd,?1H),?8.24?(t,?1H),?9.05?(d,?1H),?9.07?(d,?1H)。
Embodiment 91A
5-fluoro-7-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl) quinoxaline
Under argon atmospher, 750 milligrams of (0.819 mmoles) three-(dibenzylidene-acetone)-two palladium (0) and 551 milligrams of (1.966 mmole) tricyclohexyl phosphines are dissolved in 80 milliliters of dioxanes.Add 3814 milligrams of (15.019 mmoles) 4,4,4'4'5,5,5'5'-prestox-2,2'-is two-1,3,2-two oxa-borines, 3100 milligrams (13.654 mmole) from the compound of embodiment 90A and 2010 milligrams of (20.4813 mmole) potassium acetates and with this mixture 80 ℃ of following stirred overnight.After cooling, dioxane added in the reaction mixture and with it on diatomite, filter.Filtrate is concentrating under reduced pressure and dry under high vacuum in rotatory evaporator.We obtain 7.08 gram crude products (according to GC-MS, purity 69%), and it is without the further reaction of further purifying promptly.
GC-MS (method 6): R
t=6.78 min; MS (EIpos): m/z=274 [M]
+
Embodiment 92A
Methyl-2-{[4-(8-fluorine quinoxalin-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } the benzene carboxylic acid ester
69 milligrams of (0.075 mmoles) three-(dibenzylidene-acetone)-two palladium (0) and 50 milligrams of (0.180 mmole) tricyclohexyl phosphines are added in the crude product of 2.054 grams from embodiment 91A.It is found time also to ventilate with argon gas in each case for 5 times.Add 4 milliliters of dioxanes, 0.600 subsequently and restrain (1.499 mmole) compound and 2 milliliter of 1.27 M potassiumphosphate aqueous solution from embodiment 69A.It was stirred 2 hours down at 100 ℃.After cooling, add dioxane and it is filtered on diatomite.Purify with the filtrate evaporation concentration and by preparing HPLC (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 661 milligrams (94% of theoretical value is with respect to embodiment 69A).
LC-MS (method 4): R
t=1.37 min; MS (EIpos): m/z=468 [M+H]
+
Embodiment 93A
Methyl-2-{[4-(8-fluorine quinoxalin-6-yl)-3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl] amino } the benzene carboxylic acid ester
59 milligrams of (0.065 mmoles) three-(dibenzylidene-acetone)-two palladium (0) and 44 milligrams of (0.155 mmole) tricyclohexyl phosphines are added in the crude product of 1.774 grams from embodiment 91A.It is found time also to ventilate with argon gas in each case for 5 times.Add 3.5 milliliters of dioxanes, 0.500 subsequently and restrain (1.294 mmole) compound and 1.7 milliliter of 1.27 M potassiumphosphate aqueous solution from embodiment 72A.It was stirred 2 hours down at 100 ℃.After cooling, add entry and it is used ethyl acetate extraction.The organic phase that merges concentrates through dried over sodium sulfate and in rotatory evaporator.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 284 milligrams (theoretical values 48%).
LC-MS (method 2): R
t=2.36 min; MS (EIpos): m/z=454 [M+H]
+
Embodiment 94A
2,3-two fluoro-6-N-methyl-p-nitroanilines
With 10.00 gram (56.471 mmoles) 2,3, the 4-trifluoronitrobenzene is dissolved in the 2M methanolic ammonia solution and heated 2 hours down at 70 ℃ in autoclave.After cooling, in rotatory evaporator, remove and desolvate and residue is dissolved in the ethyl acetate.Organic phase washes with water, concentrates through dried over sodium sulfate and in rotatory evaporator.Make the gained solid from 120 ml methanol/water (recrystallization the v/v=1:1).We obtain the target compound of 7.21 grams (theoretical value 73%).
GC-MS (method 6): R
t=4.10 min; MS (EIpos): m/z=174 [M]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?6.72?(dt,?1H),?7.53?(sbr,?2H),?7.93?(ddd,?1H)。
Embodiment 95A
4-bromo-2,3-two fluoro-6-N-methyl-p-nitroanilines
With 4.00 grams (22.974 mmole) from the compound dissolution of embodiment 94A in 65 milliliters of DMF and add 5.15 gram (28.948 mmole) N-bromosuccinimides.Reaction soln was stirred 1 hour down at 90 ℃.After cooling, mixture is placed frozen water and uses ethyl acetate extraction.Organic phase water that merges and saturated nacl aqueous solution washing concentrate through dried over sodium sulfate and in rotatory evaporator.Residue is dissolved in the ethyl acetate and with organic phase water and saturated sodium-chloride water solution washing.Organic phase concentrates through dried over sodium sulfate and in rotatory evaporator.We obtain the target compound of 5.63 grams (theoretical value 97%).
GC-MS (method 6): R
t=5.30 min; MS (EIpos): m/z=252 [M]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?7.69?(sbr,?2H),?8.17?(dd,?1H)。
Embodiment 96A
5-bromo-3,4-two fluorobenzene-1,2-diamines
With 5.00 grams (19.762 mmole) from the compound dissolution of embodiment 95A in 110 milliliters of ethanol and add 17.84 gram (79.049 mmole) two hydration tin chlorides (II).With reaction soln 70 ℃ of following stirred overnight.After cooling, make it be weakly alkaline with its dilute with water and with saturated sodium bicarbonate aqueous solution.In rotatory evaporator, from this mixture, remove ethanol, this mixture is filtered on diatomite, wash with ethyl acetate again.Remove ethyl acetate extraction three times of organic phase and water.The organic phase that merges concentrates through dried over sodium sulfate and in rotatory evaporator.This residue is dry under high vacuum.We obtain the target compound of 3.96 grams (theoretical value 87%).
LC-MS (method 10): R
t=0.81 min; MS (EIpos): m/z=223 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?4.89?(sbr,?2H),?4.92?(sbr,?2H),?6.51?(dd,?1H)。
Embodiment 97A
7-bromo-5,6-difluoro quinoxaline
With 3.91 grams (17.532 mmole) from the compound dissolution of embodiment 96A in 230 milliliters of ethanol, add 2.85 gram (22.768 mmoles) 2,3-dihydroxyl-1,4-dioxane and with its stirred overnight at room temperature.This reaction mixture is concentrated in rotatory evaporator, go out product in this crystallization.It is cooled off with frozen water, leach product and drying under vacuum.We obtain the target compound of 3.04 grams (theoretical value 71%).
LC-MS (method 10): R
t=0.92 min; MS (EIpos): m/z=245 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?8.46?(dd,?1H),?9.06-9.09?(m,?2H)。
Embodiment 98A
5,6-two fluoro-7-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl) quinoxaline
Under argon atmospher, 333 milligrams of (0.364 mmoles) three-(dibenzylidene-acetone)-two palladium (0) and 245 milligrams of (0.874 mmole) tricyclohexyl phosphines are dissolved in 40 milliliters of dioxanes.It was at room temperature stirred 30 minutes.Add 1695 milligrams of (6.675 mmoles) 4 subsequently, 4,4'4'5,5,5'5'-prestox-2,2'-is two-1,3,2-two oxa-borines, 1487 milligrams (6.069 mmole) from the compound of embodiment 97A and 893 milligrams of (9.103 mmole) potassium acetates and with this mixture 80 ℃ of following stirred overnight.After cooling, reaction mixture is concentrated in rotatory evaporator, be dissolved in the methylene dichloride and on diatomite and filter.Filtrate is concentrating under reduced pressure and dry under high vacuum in rotatory evaporator.We obtain 3.36 gram crude products (according to GC-MS, purity 45%), and it promptly is used for subsequently experiment without further purification.
GC-MS (method 6): R
t=6.80 min; MS (EIpos): m/z=292 [M]
+
Embodiment 99A
Methyl-2-{[4-(7,8-difluoro quinoxalin-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } the benzene carboxylic acid ester
29 milligrams of (0.031 mmoles) three-(dibenzylidene-acetone)-two palladium (0) and 21 milligrams of (0.075 mmole) tricyclohexyl phosphines are added in 608 milligrams of crude products from embodiment 98A.It is found time also to ventilate with argon gas in each case for 5 times.Add 2 milliliters of dioxanes, 250 milligrams (0.625 mmole) the compound and 840 microlitres, the 1.27 M potassiumphosphate aqueous solution subsequently from embodiment 69A.With it 100 ℃ of following stirred overnight.After cooling, add entry and it is used ethyl acetate extraction.The organic phase that merges concentrates through dried over sodium sulfate and in rotatory evaporator.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 150 milligrams (theoretical values 19%), are 38% according to the purity of LC-MS.
LC-MS (method 4): R
t=1.42 min; MS (EIpos): m/z=486 [M+H]
+
Embodiment 100A
Methyl-2-{[4-(7,8-difluoro quinoxalin-6-yl)-3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl] amino } the benzene carboxylic acid ester
32 milligrams of (0.035 mmoles) three-(dibenzylidene-acetone)-two palladium (0) and 23 milligrams of (0.083 mmole) tricyclohexyl phosphines are added in the crude product of 1.02 grams from embodiment 98A.It is found time 5 times and ventilate with argon gas.Add 2 milliliters of dioxanes, 269 milligrams (0.696 mmole) compound and 930 microlitres, 1.27 M potassium phosphate solutions subsequently from embodiment 72A.With it 100 ℃ of following stirred overnight.After cooling, add entry and it is used ethyl acetate extraction.The organic phase that merges concentrates through dried over sodium sulfate and in rotatory evaporator.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 148 milligrams (theoretical values 39%), are 86% according to the purity of LC-MS.
LC-MS (method 2): R
t=2.46 min; MS (EIpos): m/z=472 [M+H]
+
Embodiment 101A
N-(4-bromopyridine-2-yl)-N'-hydroxyl acylimino carboxamide hydrochloride
Be suspended in 5.00 gram (28.899 mmole) 2-amino-4-bromopyridines in 10 milliliters of Virahols and at room temperature dropwise add 4.48 gram (37.568 mmole) dimethyl formamide-dimethylacetals.This mixture is boiling 2 hours (bathing 90 ℃ of temperature) under refluxing.It is cooled to 50 ℃, and adding 2.61 restrains (37.568 mmole) hydroxylamine hydrochlorides and it was stirred 10 minutes down at 50 ℃.Make it restore to room temperature, leach gained throw out and residue is dry under high vacuum.We obtain the target compound of 4.37 grams (theoretical value 57%).
LC-MS (method 10): R
t=0.67 min; MS (EIpos): m/z=216 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?7.07?(dd,?1H),?7.32?(d,?1H),?7.81?(d,?1H),?8.03?(d,?1H),?8.45?(sbr,?1H),?9.55?(d,?1H),?10.24?(s,?1H)。
Embodiment 102A
7-bromine [1,2,4] triazolo [1,5-a] pyridine
The compound of 4.00 grams (15.176 mmole) from embodiment 101A is suspended among 60 milliliters of THF.With its on the ice bath cooling and in 10 minutes, dropwise add 3.51 the gram (16.694 mmole) trifluoroacetic anhydrides so that internal temperature is no more than 20 ℃.Remove ice bath and with reaction mixture stirred overnight at room temperature.Add 200 milliliters of saturated sodium bicarbonate aqueous solutions and with it with t-butyl methyl ether extraction three times.The organic phase that merges is washed with saturated sodium bicarbonate aqueous solution, concentrates through dried over sodium sulfate and in rotatory evaporator.We obtain the target compound of 2.85 grams (theoretical value 76%), are 80% according to the purity of LC-MS.In order to analyze, will purify by preparing HPLC on a small quantity (eluent: acetonitrile/water, gradient 10:90 → 90:10).
LC-MS (method 4) R
t=0.61 min; MS (EIpos): m/z=198 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?7.39?(dd,?1H),?8.23-8.25?(m,?1H),?8.54?(s,?1H),?8.94?(d,?1H)。
Embodiment 103A
7-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl) [1,2,4] triazolo [1,5-a] pyridine
Under argon atmospher, 277 milligrams of (0.303 mmoles) three-(dibenzylidene-acetone)-two palladium (0) and 204 milligrams of (0.727 mmole) tricyclohexyl phosphines are dissolved in 30 milliliters of dioxanes.It was at room temperature stirred 30 minutes.Add 1411 milligrams of (5.555 mmoles) 4 subsequently, 4,4'4'5,5,5'5'-prestox-2,2'-is two-1,3,2-two oxa-borines, 1000 milligrams (5.050 mmole) from the compound of embodiment 102A and 743 milligrams of (7.575 mmole) potassium acetates and with this mixture 80 ℃ of following stirred overnight.After cooling, reaction mixture is concentrated in rotatory evaporator, be dissolved in the methylene dichloride and on diatomite and filter.Filtrate is concentrating under reduced pressure and dry under high vacuum in rotatory evaporator.We obtain 2415 milligrams of crude products (according to GC-MS, purity 58%), and it promptly is used for subsequently experiment without further purification.
GC-MS (method 6): R
t=6.33 min; MS (EIpos): m/z=245 [M]
+
Embodiment 104A
Methyl-2-{[3-methyl isophthalic acid-(2-aminomethyl phenyl)-4-([1,2,4] triazolo [1,5-a] pyridine-7-yl)-1H-pyrazoles-5-yl] amino } the benzene carboxylic acid ester
40 milligrams of (0.044 mmoles) three-(dibenzylidene-acetone)-two palladium (0) and 29 milligrams of (0.105 mmole) tricyclohexyl phosphines are added in 1225 milligrams of crude products from embodiment 103A.It is found time 5 times and ventilate with argon gas.Add 2.5 milliliters of dioxanes, 350 milligrams (0.874 mmole) compound and 1.17 milliliter of 1.27 M potassiumphosphate aqueous solution subsequently from embodiment 69A.It was stirred 3 hours down at 100 ℃.After cooling, add entry and it is used ethyl acetate extraction.The organic phase that merges concentrates through dried over sodium sulfate and in rotatory evaporator.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 205 milligrams (theoretical values 53%).
LC-MS (method 10): R
t=1.07 min; MS (EIpos): m/z=439 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.16?(s,?3H),?2.47?(s,?3H),?3.80?(s,?3H),?6.46?(d,?1H),?6.63?(t,?1H),?7.16-7.32?(m,?5H),?7.40?(d,?1H),?7.68?(dd,?1H),?8.44?(s,?1H),?8.88?(d,?1H),?9.21?(s,?1H)。
Embodiment 105A
Ethyl-[(5-bromopyridine-2-yl) carbamothioyl] carbamate
Be dissolved in 1.00 gram (5.780 mmole) 2-amino-5-bromopyridines in 20 milliliters of dioxanes and at room temperature dropwise add 0.76 gram (5.780 mmole) isothiocyanic acid-ethyl-carbonate.It was at room temperature stirred 15 hours, subsequently this mixture is concentrated in rotatory evaporator.Residue is dissolved in the amount of ethyl acetate and on silica gel filters.It contains product again with ethyl acetate washing and merging cut concentrates through dried over sodium sulfate and in rotatory evaporator.This residue is dry under high vacuum.We obtain the target compound of 8.70 grams (theoretical value 99%).
LC-MS (method 10): R
t=1.07 min; MS (EIpos): m/z=305 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?1.26?(t,?3H),?4.23?(q,?2H),?8.13?(dd,?1H),?8.54?(d,?1H),?8.62?(sbr,?1H),?11.71?(sbr,?1H),?12.19?(s,?1H)。
Embodiment 106A
6-bromine [1,2,4] triazolo [1,5-a] pyridine-2-amine
With 12.83 gram (184.632 mmole) hydroxylamine hydrochlorides and 14.32 gram (110.779 mmole) N, the N-diisopropylamine is dissolved in 70 ml methanol/ethanol (among the v/v=1:1).Adding 10.4 grams at room temperature stirred 2 hours from the compound of embodiment 105A and with this mixture and stirred 3 hours down at 60 ℃.After cooling, add entry and ethyl acetate, remove organic phase, twice of ethyl acetate extraction of water.The organic phase that merges is through dried over sodium sulfate, and is concentrated and residue is dry under high vacuum in rotatory evaporator.We obtain the target compound of 7.02 grams (theoretical value 96%).
GC-MS (method 6): R
t=6.11 min; MS (EIpos): m/z=212 [M]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?6.13?(s,?2H),?7.33?(d,?1H),?7.55?(dd,?1H),?8.92?(d,?1H)。
Embodiment 107A
6-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl) [1,2,4] triazolo [1,5-a] pyridine-2-amine
Under argon atmospher, 1.238 gram (1.352 mmole) three-(dibenzylidene-acetone)-two palladiums (0) and 0.910 gram (3.246 mmole) tricyclohexyl phosphine are dissolved in 140 milliliters of dioxanes.It was at room temperature stirred 30 minutes.Add 6.296 gram (24.792 mmoles) 4 subsequently, 4,4'4'5,5,5'5'-prestox-2,2'-is two-1,3,2-two oxa-borines, 4.860 grams (22.539 mmole) from the compound of embodiment 106A and 3.318 gram (33.808 mmole) potassium acetates and with this mixture 80 ℃ of following stirred overnight.After cooling, dioxane added in the reaction mixture and with it on diatomite, filter.Filtrate is concentrating under reduced pressure and dry under high vacuum in rotatory evaporator.We obtain 18.1 gram crude products (according to GC-MS, purity 4%), and it promptly is used for subsequently experiment without further purification.
GC-MS (method 6): R
t=7.49 min; MS (EIpos): m/z=260 [M]
+
Embodiment 108A
Methyl-2-{[4-(2-amino [1,2,4] triazolo [1,5-a] pyridine-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } the benzene carboxylic acid ester
Under argon atmospher, with 250 milligrams (0.625 mmoles) from the compound dissolution of embodiment 69A in 5.5 milliliters of DMF and add 3000 milligrams of crude product and 1.3 milliliters of (4.196 mmole) 2N sodium carbonate solutions from embodiment 107A.Add 43 milligrams of (0.037 mmoles) four (triphenyl phosphine) palladiums (0) and reaction mixture is descended heating 4 hours at 110 ℃.After cooling, add ethyl acetate and separate organic phase.Organic phase washes with water, concentrates through dried over sodium sulfate and in rotatory evaporator.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 43 milligrams (theoretical values 15%).
LC-MS (method 4): R
t=1.12 min; MS (EIpos): m/z=454 [M+H]
+
Embodiment 109A
Ethyl-[(4-bromopyridine-2-yl) carbamothioyl] carbamate
Be dissolved in 5.00 gram (28.899 mmole) 2-amino-4-bromopyridines in 100 milliliters of dioxanes and at room temperature dropwise add 3.79 gram (28.899 mmole) isothiocyanic acid-ethyl-carbonates.It was at room temperature stirred 15 hours, subsequently this mixture is concentrated in rotatory evaporator.Residue is dissolved in the amount of ethyl acetate and on silica gel filters.It contains product again with ethyl acetate washing and merging cut concentrates through dried over sodium sulfate and in rotatory evaporator.This residue is dry under high vacuum.We obtain the target compound of 8.60 grams (theoretical value 98%).
LC-MS (method 10): R
t=1.06 min; MS (EIpos): m/z=304 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?1.27?(t,?3H),?4.23?(q,?2H),?7.53?(dd,?1H),?8.31?(d,?1H),?8.91?(sbr,?1H),?11.84?(sbr,?1H),?12.21?(s,?1H)。
Embodiment 110A
7-bromine [1,2,4] triazolo [1,5-a] pyridine-2-amine
With 10.61 gram (152.677 mmole) hydroxylamine hydrochlorides and 11.84 gram (91.606 mmole) N, the N-diisopropylamine is dissolved in 60 ml methanol/ethanol (among the v/v=1:1).Adding 8.6 grams (28.273 mmole) at room temperature stirred 2 hours from the compound of embodiment 109A and with this mixture and stirred 3 hours down at 60 ℃.After cooling, add entry and ethyl acetate, remove organic phase, twice of ethyl acetate extraction of water.The organic phase that merges is through dried over sodium sulfate, and is concentrated and residue is dry under high vacuum in rotatory evaporator.We obtain the target compound of 4.05 grams (theoretical value 59%), and according to LC-MS, purity is 87%.
LC-MS (method 10): R
t=0.50 min; MS (EIpos): m/z=213 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?6.13?(s,?2H),?7.02?(dd,?1H),?7.65?(dd,?1H),?8.49?(dd,?1H)。
Embodiment 111A
7-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl) [1,2,4] triazolo [1,5-a] pyridine-2-amine
Under argon atmospher, 0.686 gram (0.749 mmole) three-(dibenzylidene-acetone)-two palladium (0) and 0.504 gram (1.798 mmole) tricyclohexyl phosphine are dissolved in 75 milliliters of dioxanes.It was at room temperature stirred 30 minutes.Add 3.488 gram (13.734 mmoles) 4 subsequently, 4,4'4'5,5,5'5'-prestox-2,2'-is two-1,3,2-two oxa-borines, 2.660 grams (12.486 mmole) from the compound of embodiment 110A and 1.838 gram (18.729 mmole) potassium acetates and with this mixture 80 ℃ of following stirred overnight.After cooling, dioxane added in the reaction mixture and with it on diatomite, filter.Filtrate is concentrating under reduced pressure and dry under high vacuum in rotatory evaporator.We obtain 9.300 gram crude products (according to GC-MS, purity 25%), and it promptly is used for subsequently experiment without further purification.
GC-MS (method 6): R
t=7.54 min; MS (EIpos): m/z=260 [M]
+
Embodiment 112A
Methyl-2-{[4-(2-amino [1,2,4] triazolo [1,5-a] pyridine-7-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } the benzene carboxylic acid ester
Under argon atmospher, with 250 milligrams (0.625 mmoles) from the compound dissolution of embodiment 69A in 5.5 milliliters of DMF and add 3000 milligrams of crude product and 1.3 milliliters of (4.196 mmole) 2N aqueous sodium carbonates from embodiment 111A.Add 43 milligrams of (0.037 mmoles) four (triphenyl phosphine) palladiums (0) and reaction mixture is descended heating 4 hours at 110 ℃.After cooling, add ethyl acetate and separate organic phase.Organic phase washes with water, concentrates through dried over sodium sulfate and in rotatory evaporator.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 159 milligrams (theoretical values 56%).
LC-MS (method 10): R
t=0.97 min; MS (EIpos): m/z=454 [M+H]
+
Embodiment 113A
Methyl-2-{[4-(1-aminoisoquinoline-7-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } the benzene carboxylic acid ester
Stage 1
Under argon atmospher, with 500 milligrams of (2.241 mmole) 7-bromo-isoquinoline 99.9-1-amine [people such as Rewinkel,
Bioorg. Med. Chem. Lett.1999,9,2837] be dissolved in 4 milliliters of dioxanes.Add 660 milligrams of (6.72 mmole) potassium acetates, 146 milligrams of (0.179 mmoles) 1 subsequently, 1'-pair-(diphenylphosphino) ferrocene-Palladous chloride (II)-methylene dichloride complex compound and 626 milligrams of (2.465 mmoles) 4,4,4'4'5,5,5'5'-prestox-2,2'-two-1,3,2-two oxa-borines.With this reaction mixture stirred overnight under 130 ℃ oil bath temperature.After cooling, add methylene dichloride and it is filtered on diatomite.It washs with ethyl acetate subsequently again.Filtrate is concentrating under reduced pressure and dry under high vacuum in rotatory evaporator.We obtain 776 milligrams of 7-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl) isoquinoline 99.9-1-amine [63%, (LC-MS)] as crude product.Even subsequently without its reaction of further purifying.
Stage 2
Under argon atmospher, with 388 milligrams of thus obtained 7-(4,4,5,5-tetramethyl--1,3,2-two oxa-s borine-2-yl) isoquinoline 99.9-1-amine crude product is dissolved in 4 milliliters of dioxanes with 383 milligrams of (0.958 mmole) embodiment 69A, 32.2 milligrams of (0.115 mmole) tricyclohexyl phosphines, 43.8 milligrams of (0.048 mmole) three (dibenzylidene-acetone)-two palladiums and 1.63 milliliters of (1.63 mmole) 1M potassium phosphate solutions.It is reacted whole night under reflux temperature.In rotatory evaporator, remove volatile constituent and residue subsequently by the preparation HPLC (eluent: acetonitrile/water, gradient 10:90 → 90:10) of purifying.We obtain the target compound of 100 milligrams (theoretical values 23%).
LC-MS (method 4): R
t=1.06 min; MS (EIpos): m/z=464 [M+H]
+
Embodiment 114A
6-bromo-8-fluorine quinoline
Preparation and homogenizing 5.00 gram (26.3 mmole) 4-bromo-2-fluoroanilines, 5.31 gram (57.89 mmole) glycerine and 9.89 gram (43.94 mmole) 3-nitrophenyl sulfonic acid-sodium salts.Dropwise add 25 milliliter of 70% sulfuric acid subsequently.With this mixture 135 ℃ of following stirred overnight.Carefully and under ice-cooled situation, make refrigerative black reaction mixture be alkalescence with 50% sodium hydroxide solution, on big silica gel and bed of diatomaceous earth, filter subsequently.It is water and ethyl acetate washing again.Merging mutually with collecting separates organic phase subsequently.The water that stays is used ethyl acetate extraction (2x) subsequently.Merge thus obtained organic phase subsequently with mutually isolating in advance.It removes volatile constituent through dried over mgso and in rotatory evaporator.Residue is at last by MPLC purification (Puriflash Analogix:40M: isohexane/ethyl acetate=4/1).We obtain the target compound of 3.56 grams (theoretical value 60%).
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?7.70?(dd,?2H),?7.89?(dd,?1H),?8.17?(s,?1H),?8.44?(d,?1H),?9.00?(d,?1H)。
Embodiment 115A
Methyl-2-{[4-(8-fluorine quinoline-6-yl)-3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl] amino } the benzene carboxylic acid ester
Stage 1
Under argon atmospher, 1.00 gram (4.42 mmole) embodiment 114A are dissolved in 20 milliliters of dioxanes.Add 1.302 gram (13.27 mmole) potassium acetates, 289 milligrams of (0.354 mmoles) 1 subsequently, 1'-pair-(phenylbenzene-phosphino-) ferrocene-Palladous chloride (II)-methylene dichloride complex compound and 1.69 gram (6.64 mmoles) 4,4,4'4'5,5,5'5'-prestox-2,2'-two-1,3,2-two oxa-borines.With this reaction mixture stirred overnight under 130 ℃ oil bath temperature.After cooling, add methylene dichloride and it is filtered on diatomite.It washs with ethyl acetate subsequently again.Filtrate is concentrating under reduced pressure and dry under high vacuum in rotatory evaporator.We obtain 2.01 gram 8-(fluorine quinoline-6-yl) boric acid [73%, (LC-MS)] as crude product.Even subsequently without its reaction of further purifying.
Stage 2
Under argon atmospher, 148 milligrams of thus obtained 8-(fluorine quinoline-6-yl) boric acid crude product is dissolved in 3 milliliters of dioxanes with 200 milligrams of (0.518 mmole) embodiment 72A, 174 milligrams of (0.621 mmole) tricyclohexyl phosphines, 24 milligrams of (0.026 mmole) three (dibenzylidene-acetone)-two palladiums and 0.880 milliliter of (0.880 mmole) 1M potassium phosphate solution.It is reacted whole night under reflux temperature.In rotatory evaporator, remove volatile constituent and residue subsequently by the preparation HPLC (eluent: acetonitrile/water, gradient 10:90 → 90:10) of purifying.We obtain the target compound of 73 milligrams (theoretical values 31%).
LC-MS (method 10): R
t=1.21 min; MS (EIpos): m/z=453 [M+H]
+
Embodiment 116A
7-bromo-4-methoxy quinoline
With 500 milligrams of (2.06 mmole) 7-bromo-4-chloroquinoline [people such as De,
J. Med. Chem.1998,41,4918] be dissolved in 3 milliliters of dioxanes.Being added in the gram of 1.86 in 3 ml methanol (10.31 mmole) sodium methylate subsequently also reacted 60 minutes down at 120 ℃ in the single mode microwave subsequently.Filter this mixture and wash with small amount of methanol.After drying, obtain the target compound of 250 milligrams (theoretical values 51%).
LC-MS (method 2): R
t=1.19 min; MS (EIpos): m/z=238 [M]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?7.09?(d,?1H),?7.70?(dd,?1H),?8.08?(d,?1H),?8.16?(d,?1H),?8.77?(s,?1H)。
Embodiment 117A
Methyl-2-{[4-(4-methoxy quinoline-7-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } the benzene carboxylic acid ester
Stage 1
Under argon atmospher, 250 milligrams of (1.05 mmole) embodiment 116A are dissolved in 5 milliliters of dioxanes.Add 185 milligrams of (1.89 mmole) potassium acetates, 68 milligrams of (0.084 mmoles) 1 subsequently, 1'-pair-(phenylbenzene-phosphino-) ferrocene-Palladous chloride (II)-methylene dichloride complex compound and 293 milligrams of (1.16 mmoles) 4,4,4'4'5,5,5'5'-prestox-2,2'-two-1,3,2-two oxa-borines.With this reaction mixture stirred overnight under 130 ℃ oil bath temperature.After cooling, add methylene dichloride and it is filtered on diatomite.It washs with ethyl acetate subsequently again.Filtrate is concentrating under reduced pressure and dry under high vacuum in rotatory evaporator.We obtain 560 milligrams of (4-methoxy quinoline-7-yl) boric acid [94%, (LC-MS)] as crude product.Even subsequently without its reaction of further purifying.
Stage 2
Under argon atmospher, 202 milligrams of thus obtained (4-methoxy quinoline-7-yl) boric acid crude products are dissolved in 7.5 milliliters of dioxanes with 300 milligrams of (0.749 mmole) embodiment 69A, 25.2 milligrams of (0.090 mmole) tricyclohexyl phosphines, 34.3 milligrams of (0.037 mmole) three (dibenzylidene-acetone)-two palladiums and 1.274 milliliters of (1.274 mmole) 1M potassiumphosphate aqueous solution.It is reacted whole night under reflux temperature.In rotatory evaporator, remove volatile constituent and residue subsequently by the preparation HPLC (eluent: acetonitrile/water, gradient 10:90 → 90:10) of purifying.We obtain the target compound of 130 milligrams (theoretical values 36%).
LC-MS (method 10): R
t=0.96 min; MS (EIpos): m/z=479 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.17?(s,?3H),?2.45?(s,?3H),?3.79?(s,?3H),?4.01?(s,?3H),?6.47?(d,?1H),?6.59?(t,?1H),?6.97?(d,?1H),?7.15?(t,?1H),?7.23?(mc,?1H),?7.27-7.35?(m,?2H),?7.42?(d,?1H),?7.66?(d,?2H),?7.96?(s,?1H),?8.04?(d,?1H),?8.68?(d,?1H),?9.19?(s,?1H)。
Embodiment 118A
7-bromo-5-fluquinconazole quinoline
With 1000 milligrams of (4.53 mmole) 4-bromo-2, the 6-difluorobenzaldehyde [people such as Wang,
Org. Lett.2007,9,5629] be dissolved in 30 milliliters of acetonitriles.It uses the argon gas rinsing subsequently, adds 659 milligrams of (6.34 mmole) salt of wormwood and 800 milligrams of active molecular sieves (4) subsequently.Subsequently with its stirred overnight under reflux temperature.After its cooling, reaction mixture is filtered on diatomite.It washs with ethyl acetate again.In rotatory evaporator, remove volatile constituent subsequently.This residue is finally by MPLC purification (Puriflash Analogix:40M: isohexane/ethyl acetate=4/1).We obtain the target compound of 331 milligrams (theoretical values 32%).
GC-MS:(method 6): R
t=4.57 min; MS (EIpos): m/z=228 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?7.96?(dd,?1H),?8.18?(s,?1H),?9.42?(s,?1H),?9.76?(s,?1H)。
Embodiment 119A
Methyl-2-{[4-(5-fluquinconazole quinoline-7-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } benzoic ether
Under argon atmospher, 331 milligrams of (1.46 mmole) embodiment 118A are dissolved in 10 milliliters of dioxanes.Add 429 milligrams of (4.37 mmole) potassium acetates, 95.2 milligrams of (0.117 mmoles) 1 subsequently, 1'-pair-(diphenylphosphino)-ferrocene Palladous chloride (II)-methylene dichloride complex compound and 407 milligrams of (1.64 mmoles) 4,4,4'4'5,5,5'5'-prestox-2,2'-two-1,3,2-two oxa-borines.With reaction mixture stirred overnight under 110 ℃ oil bath temperature.After cooling, add methylene dichloride and it is filtered on diatomite.It washs with ethyl acetate again.Filtrate is concentrating under reduced pressure and dry under high vacuum in rotatory evaporator subsequently.Under argon atmospher, thus obtained crude product is dissolved in 10 milliliters of dioxanes with 862 milligrams of (2.16 mmole) embodiment 69A, 72.5 milligrams of (0.259 mmole) tricyclohexyl phosphines, 98.6 milligrams of (0.108 mmole) three (dibenzylidene-acetone)-two palladiums and 3.67 milliliters of (3.67 mmole) 1M potassium phosphate solutions.It is reacted whole night down at 100 ℃.With the reaction mixture evaporation concentration, on the silica gel bed, carry out post subsequently and filter.In rotatory evaporator, remove volatile constituent and separate this reaction mixture (eluent: acetonitrile/water, gradient 10:90 → 90:10) by preparation HPLC.For separating by-products, it is at last by MPLC (the Puriflash Analogix:40M: isohexane/ethyl acetate=10/1-1/1) that purifies again.We obtain the target compound of 155 milligrams (15% of theoretical value is with respect to embodiment 69A).
LC-MS (method 10): R
t=1.24 min; MS (EIpos): m/z=468 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.18?(s,?3H),?3.81?(s,?3H),?6.46?(d,?1H),?6.61?(t,?1H),?7.16?(mc,?1H),?7.25?(m,?1H),?7.29-7.35?(m,?2H),?7.42?(d,?1H),?7.67?(dd,?1H),?7.74?(d,?1H),?7.91?(s,?1H),?9.25?(s,?1H),?9.32?(s,?1H),?9.63?(s,?1H)。
Embodiment 120A
3-methyl isophthalic acid-[2-(trifluoromethyl) phenyl]-1H-pyrazoles-5-amine
Preparation 2.789 restrains (15.83 mmole) 2-(trifluoromethyl)-phenyl hydrazine and adds the amino propenyl cyanides of 1.378 gram (16.781 mmole) 3-in 15 milliliters of 1N hydrochloric acid.This mixture was stirred 18 hours down at 100 ℃.After cooling, the pH value of this mixture is adjusted to pH with the 1N sodium hydroxide solution〉12.It is used dichloromethane extraction three times.The organic phase that merges is washed with saturated sodium-chloride water solution, through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.This product is dry under high vacuum also purifies by preparing HPLC (eluent: acetonitrile/water, gradient 20:80 → 90:10).We obtain the target compound of 2.500 grams (60% of theoretical value, according to HPLC, purity 91%).
LC-MS (method 10): R
t=1.09 min; MS (EIpos): m/z=242 [M+H]
+
Embodiment 121A
Methyl-2-({ 3-methyl isophthalic acid-[2-(trifluoromethyl) phenyl]-1H-pyrazoles-5-yl } amino) benzoic ether
Under argon atmospher, be dissolved in 2.430 gram (10.074 mmole) 3-methyl isophthalic acid-[2-(trifluoromethyl) phenyl]-1H-pyrazoles-5-amine (from the compound of embodiment 120A) in 30 milliliters of toluene and add 75 milligrams of (0.336 mmole) acid chlorides (II) and 0.362 restrain (0.672 mmole) two-[2-diphenylphosphino)-phenyl]-ether.This mixture was at room temperature stirred 5 minutes.Add subsequently 1.444 the gram (6.716 mmole) methyl-2-bromo-benzoates and 3.064 the gram (9.402 mmole) cesium carbonates and with this mixture 95 ℃ of following stirred overnight.After cooling, it is filtered on silica gel, with this suction filter filter cake with ethyl acetate washing and with the filtrate evaporation concentration.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 20:80 → 90:10).We obtain the target compound of 2.500 grams (theoretical value 65%).
LC-MS (method 10): R
t=1.23 min; MS (EIpos): m/z=376 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.23?(s,?3H),?3.72?(s,?3H),?6.22?(s,?1H),?6.82-6.86?(m?1H),?7.20?(d,?1H),?7.46-7.50?(m,?1H),?7.60?(d,?1H),?7.75?(t,?1H),?7.80-7.85?(m,?2H),?7.93-7.96?(m,?1H),?9.27?(s,?1H)。
Embodiment 122A
Methyl-2-({ 4-bromo-3-methyl isophthalic acid-[2-(trifluoromethyl) phenyl]-1H-pyrazoles-5-yl } amino) benzoic ether
With 2.375 grams (6.327 mmole) from the compound dissolution of embodiment 121A in 35 milliliters of methylene dichloride, and with in ice-cooled, portioning adds 0.905 and restrains (3.164 mmole) 1,3-two bromo-5,5-T10.Reaction test by HPLC shows to be finished after being reflected at 60 minutes.Add methylene dichloride, organic phase water, saturated sodium bicarbonate aqueous solution and the washing of 10% sodium thiosulfate solution.Organic phase is with after dried over sodium sulfate and concentrating in rotatory evaporator.We obtain the target compound of 2.800 grams (theoretical value 97%).
LC-MS (method 2): R
t=2.72 min; MS (EIpos): m/z=456 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.26?(s,?3H),?3.79?(s,?3H),?6.58?(d,?1H),?6.81?(dt,?1H),?7.41?(dt,?1H),?7.68-7.73?(m,?2H),?7.76-7.80?(m,?2H),?7.90?(d,?1H),?9.04?(s,?1H)。
Embodiment 123A
Methyl-2-({ 4-(8-fluorine quinoxalin-6-yl)-3-methyl isophthalic acid-[2-(trifluoromethyl) phenyl]-1H-pyrazoles-5-yl } amino) benzoic ether
53 milligrams of (0.058 mmoles) three-(dibenzylidene-acetone)-two palladium (0) and 39 milligrams of (0.138 mmole) tricyclohexyl phosphines are added in the crude product of 1.186 grams from embodiment 91A.It is found time 5 times and ventilate with argon gas.Add 3.0 milliliters of dioxanes, 0.524 subsequently and restrain (1.154 mmole) compound and 1.5 milliliter of 1.27 M potassiumphosphate aqueous solution from embodiment 122A.It was stirred 2 hours down at 100 ℃.After cooling, add entry and it is used ethyl acetate extraction.The organic phase that merges concentrates through dried over sodium sulfate and in rotatory evaporator.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 400 milligrams (53% of theoretical value, purity 80%).
LC-MS (method 10): R
t=1.22 min; MS (EIpos): m/z=522 [M+H]
+
Embodiment 124A
1-(2, the 5-3,5-dimethylphenyl)-3-methyl isophthalic acid H-pyrazoles-5-amine
With 4.00 gram (23.167 mmoles) 2,5-3,5-dimethylphenyl hydrazonium salt hydrochlorate is suspended in 23 milliliters of 1N hydrochloric acid and adds the amino propenyl cyanide of 2.016 gram (24.557 mmole) 3-.This mixture stirred 18 hours down at 100 ℃.After cooling, the pH value of this mixture is adjusted to pH with the 1N sodium hydroxide solution〉12.It is used dichloromethane extraction three times.The organic phase that merges is washed with saturated sodium-chloride water solution, through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.We obtain the target compound of 4.301 grams (theoretical value 92%).
LC-MS (method 2): R
t=1.05 min; MS (EIpos): m/z=202 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.00?(s,?3H)?2.03?(s,?3H),?2.29?(s,?3H),?4.82?(s,?2H),?5.20?(s,?1H),?7.01?(s,?1H),?7.13?(dd,?1H),?7.21?(d,?1H)。
Embodiment 125A
Methyl-2-{[1-(2, the 5-3,5-dimethylphenyl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino } benzoic ether
Under argon atmospher, with 4.200 grams (20.867 mmole) from the compound dissolution of embodiment 124A in 60 milliliters of toluene and add 156 milligrams of (0.696 mmole) acid chlorides (II) and 0.749 restrain (1.391 mmole) two-[2-diphenylphosphino)-phenyl]-ether.This mixture was at room temperature stirred 5 minutes.Add subsequently 2.992 the gram (13.911 mmole) methyl-2-bromo-benzoates and 6.346 the gram (19.476 mmole) cesium carbonates and with this mixture 95 ℃ of following stirred overnight.After cooling, it is filtered on silica gel, with this suction filter filter cake with ethyl acetate washing and with the filtrate evaporation concentration.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 4.65 grams (theoretical value 66%).
LC-MS (method 10): R
t=1.29 min; MS (EIpos): m/z=336 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?1.98?(s,?3H),?2.23?(s,?3H),?2.29?(s,?3H),?3.73?(s,?3H),?6.19?(s,?1H),?6.82-6.86?(m?1H),?7.12?(s,?1H),?7.19?(dd,?1H),?7.24-7.27?(m,?2H),?7.47-7.51?(m,?1H),?7.83?(dd,?1H),?9.28?(s,?1H)。
Embodiment 126A
Methyl-2-{[4-bromo-1-(2, the 5-3,5-dimethylphenyl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino } benzoic ether
With 4.568 grams (13.620 mmole) from the compound dissolution of embodiment 125A in 75 milliliters of methylene dichloride, and with in ice-cooled, portioning adds 1.947 and restrains (6.810 mmoles) 1,3-two bromo-5,5-T10.Reaction test by HPLC shows to be finished after being reflected at 30 minutes.Add methylene dichloride, organic phase water, saturated sodium bicarbonate aqueous solution and the washing of 10% sodium thiosulfate solution.Organic phase is with after dried over sodium sulfate and concentrating in rotatory evaporator.We obtain the target compound of 5.402 grams (theoretical value 96%).
LC-MS (method 10): R
t=1.37 min; MS (EIpos): m/z=414 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.02?(s,?3H),?2.22?(s,?3H),?2.26?(s,?3H),?3.80?(s,?3H),?6.54?(d,?1H),?6.79?(t,?1H),?7.11-7.19?(m,?3H),?7.38-7.42?(m,?1H),?7.79?(dd,?1H),?8.97?(s,?1H)。
Embodiment 127A
Methyl-2-{[1-(2, the 5-3,5-dimethylphenyl)-4-(8-fluorine quinoxalin-6-yl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino } benzoic ether
55 milligrams of (0.060 mmoles) three-(dibenzylidene-acetone)-two palladium (0) and 41 milligrams of (0.145 mmole) tricyclohexyl phosphines are added in the crude product of 1.103 grams from embodiment 91A.It is found time 5 times and ventilate with argon gas.Add 3.0 milliliters of dioxanes, 0.500 subsequently and restrain (1.207 mmole) compound and 1.6 milliliter of 1.27 M potassium phosphate solution from embodiment 126A.With it 100 ℃ of following stirred overnight.After cooling, add entry and it is used ethyl acetate extraction.The organic phase that merges concentrates through dried over sodium sulfate and in rotatory evaporator.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 395 milligrams (theoretical values 68%).
LC-MS (method 10): R
t=1.30 min; MS (EIpos): m/z=482 [M+H]
+
Embodiment 128A
1-(2,4 difluorobenzene base)-3-methyl isophthalic acid H-pyrazoles-5-amine
Be suspended in 5.040 gram (27.911 mmole) 2,4 difluorobenzene base hydrazonium salt hydrochlorates in 28 milliliters of 1N hydrochloric acid and add the amino propenyl cyanides of 2.429 gram (29.586 mmole) 3-.This mixture was stirred 18 hours down at 100 ℃.After cooling, the pH value of this mixture is adjusted to pH with the 1N sodium hydroxide solution〉12.It is used dichloromethane extraction three times.The organic phase that merges is washed with saturated sodium-chloride water solution, through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.This residue is by the silica gel chromatography (eluent: isohexane/ethyl acetate, gradient 85:15 → 10:90) of purifying.We obtain the target compound of 4.740 grams (theoretical value 81%).
LC-MS (method 4): R
t=0.52 min; MS (EIpos): m/z=210 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.03?(s,?3H),?5.14?(sbr,?2H),?5.22?(s,?1H),?7.15-7.21?(m,?1H),?7.14-7.50?(m,?2H)。
Embodiment 129A
Methyl-2-{[1-(2,4 difluorobenzene base)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino } benzoic ether
Under argon atmospher, with 2.000 grams (20.867 mmole) from the compound dissolution of embodiment 128A in 30 milliliters of toluene and add 177 milligrams of (0.319 mmole) acid chlorides (II) and 0.849 restrain (0.637 mmole) two-[2-diphenylphosphino)-phenyl]-ether.This mixture was at room temperature stirred 5 minutes.Add subsequently 1.371 the gram (6.373 mmole) methyl-2-bromo-benzoates and 7.19 the gram (8.923 mmole) cesium carbonates and with this mixture 95 ℃ of following stirred overnight.After cooling, it is filtered on silica gel, with this suction filter filter cake with ethyl acetate washing and with the filtrate evaporation concentration.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 2.23 grams (theoretical value 68%).
LC-MS (method 4): R
t=1.36 min; MS (EIpos): m/z=344 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.24?(s,?3H),?3.79?(s,?3H),?6.26?(s,?1H),?6.84?(t,?1H)?7.08?(d,?1H),?7.22-7.27?(m,?1H),?7.43-7.48?(m,?1H),?7.65?(dt,?1H),?7.84?(dd,?1H),?9.37?(s,?1H)。
Embodiment 130A
Methyl-2-{[4-bromo-1-(2,4 difluorobenzene base)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino } benzoic ether
With 2.221 grams (6.470 mmole) from the compound dissolution of embodiment 129A in 35 milliliters of methylene dichloride, and with in ice-cooled, portioning adds 0.925 and restrains (3.235 mmole) 1,3-two bromo-5,5-T10.Reaction test by HPLC shows to be finished after being reflected at 30 minutes.Add methylene dichloride, organic phase water, saturated sodium bicarbonate aqueous solution and the washing of 10% sodium thiosulfate solution.Organic phase is with after dried over sodium sulfate and concentrating in rotatory evaporator.We obtain the target compound of 2.540 grams (theoretical value 92%).
LC-MS (method 10): R
t=1.29 min; MS (EIpos): m/z=422 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.27?(s,?3H),?3.83?(s,?3H),?6.49?(d,?1H),?6.81?(t,?1H)?7.19-7.24?(m,?1H),?7.36-7.40?(m,?1H),?7.46-7.51?(m,?1H),?7.68?(dt,?1H),?7.82?(dd,?1H),?9.09?(s,?1H)。
Embodiment 131A
Methyl-2-{[1-(2,4 difluorobenzene base)-4-(8-fluorine quinoxalin-6-yl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino } benzoic ether
54 milligrams of (0.059 mmoles) three-(dibenzylidene-acetone)-two palladium (0) and 40 milligrams of (0.142 mmole) tricyclohexyl phosphines are added in the crude product of 1.082 grams from embodiment 91A.It is found time 5 times and ventilate with argon gas.Add 3.0 milliliters of dioxanes, 0.500 subsequently and restrain (1.184 mmole) compound and 1.6 milliliter of 1.27 M potassiumphosphate aqueous solution from embodiment 130A.It was stirred 5 hours down at 100 ℃.After cooling, add entry and it is used ethyl acetate extraction.The organic phase that merges concentrates through dried over sodium sulfate and in rotatory evaporator.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 488 milligrams (theoretical values 84%).
LC-MS (method 10): R
t=1.30 min; MS (EIpos): m/z=490 [M+H]
+
Embodiment 132A
1-(3-fluoro-2-aminomethyl phenyl)-3-methyl isophthalic acid H-pyrazoles-5-amine
Be suspended in 2.000 gram (11.324 mmole) 2-methyl-3-fluorophenyl hydrazonium salt hydrochlorates in 11 milliliters of 1N hydrochloric acid and add 0.986 and restrain the amino propenyl cyanide of (12.003 mmole) 3-.This mixture was stirred 18 hours down at 100 ℃.After cooling, the pH value of this mixture is adjusted to pH with the 1N sodium hydroxide solution〉12.It is used dichloromethane extraction three times.The organic phase that merges is washed with saturated sodium-chloride water solution, through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.We obtain the target compound of 1.92 grams (75% of theoretical value, according to HPLC, purity 91%).
LC-MS (method 10): R
t=0.53 min; MS (EIpos): m/z=206 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?1.97?(d,?3H),?2.04?(s,?3H),?5.00?(sbr,?2H),?5.22?(s,?1H),?7.09?(d,?1H),?7.22-7.35?(m,?2H)。
Embodiment 133A
Methyl-2-{[1-(3-fluoro-2-aminomethyl phenyl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino } benzoic ether
Under argon atmospher, with 1.90 grams (9.258 mmole) from the compound dissolution of embodiment 132A in 26 milliliters of toluene and add 69 milligrams of (0.309 mmole) acid chlorides (II) and 0.332 restrain (0.617 mmole) two-[2-diphenylphosphino)-phenyl]-ether.This mixture was at room temperature stirred 5 minutes.Add subsequently 1.327 the gram (6.172 mmole) methyl-2-bromo-benzoates and 2.815 the gram (8.640 mmole) cesium carbonates and with this mixture 95 ℃ of following stirred overnight.After cooling, it is filtered on silica gel, with this suction filter filter cake with ethyl acetate washing and with the filtrate evaporation concentration.This residue is by the silica gel chromatography (eluent: isohexane/ethyl acetate, gradient 90:10 → 10:90) of purifying.We obtain the target compound of 1.80 grams (theoretical value 57%).
LC-MS (method 10): R
t=1.26 min; MS (EIpos): m/z=340 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?1.95?(d,?3H),?2.24?(s,?3H),?3.74?(s,?3H),?6.24?(s,?1H),?6.85?(dt,?1H)?7.20-7.22?(m,?2H),?7.29-7.39?(m,?2H),?7.46-7.51?(m,?1H),?7.84?(dd,?1H),?9.30?(s,?1H)。
Embodiment 134A
Methyl-2-{[4-bromo-1-(3-fluoro-2-aminomethyl phenyl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino } benzoic ether
With 1.686 grams (4.969 mmole) from the compound dissolution of embodiment 133A in 30 milliliters of methylene dichloride, and with in ice-cooled, portioning adds 0.710 and restrains (2.484 mmole) 1,3-two bromo-5,5-T10.Reaction test by HPLC shows to be finished after being reflected at 20 minutes.Add methylene dichloride, organic phase water, saturated sodium bicarbonate aqueous solution and the washing of 10% sodium thiosulfate solution.Organic phase is with after dried over sodium sulfate and concentrating in rotatory evaporator.We obtain the target compound of 5.402 grams (theoretical value 92%).
LC-MS (method 2): R
t=2.78 min; MS (EIpos): m/z=418 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.01?(d,?3H),?2.27?(s,?3H),?3.81?(s,?3H),?6.52?(d,?1H),?6.77-6.81?(m,?1H),?7.22-7.31?(m,?3H),?7.37-7.41?(m,?1H),?7.79?(dd,?1H),?9.00?(s,?1H)。
Embodiment 135A
Methyl-2-{[4-(8-fluorine quinoxalin-6-yl)-1-(3-fluoro-2-aminomethyl phenyl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino } benzoic ether
36 milligrams of (0.039 mmoles) three-(dibenzylidene-acetone)-two palladium (0) and 26 milligrams of (0.094 mmole) tricyclohexyl phosphines are added in 537 milligrams of crude products from embodiment 91A.It is found time 5 times and ventilate with argon gas.Add 2 milliliters of dioxanes, 328 milligrams (0.784 mmole) compound and 1.05 milliliter of 1.27 M potassiumphosphate aqueous solution subsequently from embodiment 134A.It was stirred 5 hours down at 100 ℃.After cooling, add entry and it is used ethyl acetate extraction.The organic phase that merges concentrates through dried over sodium sulfate and in rotatory evaporator.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 277 milligrams (theoretical values 68%).
LC-MS (method 10): R
t=1.26 min; MS (EIpos): m/z=486 [M+H]
+
Embodiment 136A
1-(2, the 5-difluorophenyl)-3-methyl isophthalic acid H-pyrazoles-5-amine
With 5.00 gram (34.692 mmoles) 2,5-difluorophenyl hydrazine is suspended in 35 milliliters of 1N hydrochloric acid and adds the amino propenyl cyanide of 3.019 gram (36.774 mmole) 3-.This mixture was stirred 18 hours down at 100 ℃.After cooling, the pH value of this mixture is adjusted to pH with the 1N sodium hydroxide solution〉12.It is used dichloromethane extraction three times.The organic phase that merges is washed with saturated sodium-chloride water solution, through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.We obtain the target compound of 1.92 grams (theoretical value 88%).
LC-MS (method 4): R
t=0.60 min; MS (EIpos): m/z=210 [M+H]
+
Embodiment 137A
Methyl-2-{[1-(2, the 5-difluorophenyl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino } benzoic ether
Under argon atmospher, with 6.830 grams (30.363 mmole) from the compound dissolution of embodiment 136A in 90 milliliters of toluene and add 227 milligrams of (1.012 mmole) acid chlorides (II) and 1.090 restrain (2.024 mmole) two-[2-diphenylphosphino)-phenyl]-ether.This mixture was at room temperature stirred 5 minutes.Add subsequently 4.353 the gram (20.242 mmole) methyl-2-bromo-benzoates and 9.234 the gram (28.339 mmole) cesium carbonates and with this mixture 95 ℃ of following stirred overnight.After cooling, it is filtered on silica gel, with this suction filter filter cake with ethyl acetate washing and with the filtrate evaporation concentration.This residue is by the silica gel chromatography (eluent: isohexane/ethyl acetate, gradient 90:10 → 10:90) of purifying.We obtain the target compound of 8.100 grams (theoretical value 78%).
LC-MS (method 10): R
t=1.19 min; MS (EIpos): m/z=344 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.25?(s,?3H),?3.80?(s,?3H),?6.28?(s,?1H),?6.84?(t,?1H)?7.07?(d,?1H),?7.36-7.57?(m,?4H),?7.85?(dd,?1H),?9.42?(s,?1H)。
Embodiment 138A
Methyl-2-{[4-bromo-1-(2, the 5-difluorophenyl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino } benzoic ether
With 4.00 grams (11.65 mmole) from the compound dissolution of embodiment 137A in 65 milliliters of methylene dichloride, and with in ice-cooled, portioning adds 1.67 and restrains (5.825 mmoles) 1,3-two bromo-5,5-T10.Reaction test by HPLC shows to be finished after being reflected at 20 minutes.Add methylene dichloride, organic phase water, saturated sodium bicarbonate aqueous solution and the washing of 10% sodium thiosulfate solution.Organic phase is with after dried over sodium sulfate and concentrating in rotatory evaporator.We obtain the target compound of 4.50 grams (theoretical value 89%).
LC-MS (method 10): R
t=1.33 min; MS (EIpos): m/z=421 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.28?(s,?3H),?3.84?(s,?3H),?6.48?(d,?1H),?6.81?(t,?1H),?7.33-7.49?(m,?2H),?7.57-7.62?(m,?1H),?7.82?(dd,?1H),?9.13?(s,?1H)。
Embodiment 139A
Methyl-2-{[1-(2, the 5-difluorophenyl)-4-(8-fluorine quinoxalin-6-yl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino } benzoic ether
54 milligrams of (0.059 mmoles) three-(dibenzylidene-acetone)-two palladium (0) and 40 milligrams of (0.142 mmole) tricyclohexyl phosphines are added in 1.082 milligrams of crude products from embodiment 91A.It is found time also to ventilate with argon gas in each case for 5 times.Add 3 milliliters of dioxanes, 500 milligrams (1.184 mmole) compound and 1.59 milliliter of 1.27 M potassiumphosphate aqueous solution subsequently from embodiment 138A.It was stirred 2 hours down at 100 ℃.After cooling, add entry and it is used ethyl acetate extraction.The organic phase that merges concentrates through dried over sodium sulfate and in rotatory evaporator.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 430 milligrams (theoretical values 74%).
LC-MS (method 10): R
t=1.20 min; MS (EIpos): m/z=490 [M+H]
+
Embodiment 140A
1-(4-fluoro-2-aminomethyl phenyl)-3-methyl isophthalic acid H-pyrazoles-5-amine
Restrain (87.267 mmole) 4-fluoro-2-methylphenylhydrazine hydrochlorides (about preparation with 15.413, referring to WO 2007/077961, the 294th page, embodiment 107) be suspended in 90 milliliters of 1N hydrochloric acid and add the amino propenyl cyanides of 7.595 gram (92.503 mmole) 3-.This mixture was stirred 18 hours down at 100 ℃.After cooling, the pH value of this mixture is adjusted to pH with the 1N sodium hydroxide solution〉12.It is used dichloromethane extraction three times.The organic phase that merges is washed with saturated sodium-chloride water solution, through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.This residue is by the silica gel chromatography (eluent: isohexane/ethyl acetate, gradient 70:30 → 30:70) of purifying.We obtain the target compound of 10.400 grams (theoretical value 58%).
LC-MS (method 4): R
t=0.47 min; MS (EIpos): m/z=206 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.03?(s,?3H),?2.04?(s,?3H),?4.91?(s,?2H),?5.21?(s,?1H),?7.07-7.12?(m,?1H)?7.19-7.25?(m,?2H)。
Embodiment 141A
Methyl-2-{[1-(4-fluoro-2-aminomethyl phenyl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino } benzoic ether
Under argon atmospher, with 5.00 grams (24.36 mmole) from the compound dissolution of embodiment 140A in 70 milliliters of toluene and add 182 milligrams of (0.812 mmole) acid chlorides (II) and 0.875 restrain (1.624 mmole) two-[2-diphenylphosphino)-phenyl]-ether.This mixture was at room temperature stirred 5 minutes.Add subsequently 3.493 the gram (16.241 mmole) methyl-2-bromo-benzoates and 7.409 the gram (22.738 mmole) cesium carbonates and with this mixture 95 ℃ of following stirred overnight.After cooling, it is filtered on silica gel, with this suction filter filter cake with ethyl acetate washing and with the filtrate evaporation concentration.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 8.100 grams (theoretical value 78%).
LC-MS (method 10): R
t=1.24 min; MS (EIpos): m/z=340 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.02?(s,?3H),?2.23?(s,?3H),?3.74?(s,?3H),?6.21?(s,?1H),?6.84?(t,?1H)?7.16?(dt,?1H),?7.23?(d,?1H),?7.27?(dd,?1H),?7.38?(dd,?1H),?7.49?(dt,?1H),?7.84?(dd,?1H),?9.28?(s,?1H)。
Embodiment 142A
Methyl-2-{[4-bromo-1-(4-fluoro-2-aminomethyl phenyl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino } benzoic ether
With 5.006 grams (14.750 mmole) from the compound dissolution of embodiment 141A in 80 milliliters of methylene dichloride, and with in ice-cooled, portioning adds 2.109 and restrains (7.375 mmoles) 1,3-two bromo-5,5-T10.Reaction test by HPLC shows to be finished after being reflected at 20 minutes.Add methylene dichloride, organic phase water, saturated sodium bicarbonate aqueous solution and the washing of 10% sodium thiosulfate solution.Organic phase is with after dried over sodium sulfate and concentrating in rotatory evaporator.We obtain the target compound of 5.821 grams (theoretical value 94%).
LC-MS (method 4): R
t=1.52 min; MS (EIpos): m/z=418 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.08?(s,?3H),?2.26?(s,?3H),?3.81?(s,?3H),?6.54?(d,?1H),?6.79?(dt,?1H)?7.09?(dt,?1H),?7.20?(dd,?1H),?7.37-7.44?(m,?2H),?7.79?(dd,?1H),?8.97?(s,?1H)。
Embodiment 143A
Methyl-2-{[4-(8-fluorine quinoxalin-6-yl)-1-(4-fluoro-2-aminomethyl phenyl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino } benzoic ether
49 milligrams of (0.054 mmoles) three-(dibenzylidene-acetone)-two palladium (0) and 36 milligrams of (0.129 mmole) tricyclohexyl phosphines are added in 1.474 milligrams of crude products from embodiment 91A.It is found time 5 times and ventilate with argon gas.Add 3 milliliters of dioxanes, 450 milligrams (1.076 mmole) compound and 1.44 milliliter of 1.27 M potassiumphosphate aqueous solution subsequently from embodiment 142A.It was stirred 5 hours down at 100 ℃.After cooling, add entry and it is used ethyl acetate extraction.The organic phase that merges concentrates through dried over sodium sulfate and in rotatory evaporator.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 430 milligrams (theoretical values 82%).
LC-MS (method 1): R
t=2.67 min; MS (EIpos): m/z=486 [M+H]
+
Embodiment 144A
1-(2-fluoro-6-aminomethyl phenyl)-3-methyl isophthalic acid H-pyrazoles-5-amine
Be suspended in 3.682 gram (18.428 mmole) 6-fluoro-2-methylphenylhydrazine hydrochlorides (preparation is similar to 2007/077961, the 294 page of WO, and embodiment 107) in 20 milliliters of 1N hydrochloric acid and add 1.603 and restrain the amino propenyl cyanides of (19.534 mmole) 3-.This mixture was stirred 18 hours down at 100 ℃.After cooling, the pH value of this mixture is adjusted to pH with the 1N sodium hydroxide solution〉12.It is used dichloromethane extraction three times.The organic phase that merges is washed with saturated sodium-chloride water solution, through dried over sodium sulfate and in rotatory evaporator concentrating under reduced pressure.We obtain the target compound of 3.88 grams (theoretical value 100%).
LC-MS (method 10): R
t=0.51 min; MS (EIpos): m/z=206 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.02?(s,?3H),?2.04?(s,?3H),?4.98?(s,?2H),?5.22?(s,?1H),?7.15-7.19?(m,?2H)?7.36-7.41?(m,?1H)。
Embodiment 145A
Methyl-2-{[1-(2-fluoro-6-aminomethyl phenyl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino } benzoic ether
Under argon atmospher, with 2.00 grams (9.745 mmole) from the compound dissolution of embodiment 144A in 30 milliliters of toluene and add 73 milligrams of (0.325 mmole) acid chlorides (II) and 0.350 restrain (0.650 mmole) two-[2-diphenylphosphino)-phenyl]-ether.This mixture was at room temperature stirred 5 minutes.Add subsequently 1.397 the gram (6.497 mmole) methyl-2-bromo-benzoates and 2.963 the gram (9.095 mmole) cesium carbonates and with this mixture 95 ℃ of following stirred overnight.After cooling, it is filtered on silica gel, with this suction filter filter cake with ethyl acetate washing and with the filtrate evaporation concentration.This residue is by the silica gel chromatography (eluent: isohexane/ethyl acetate, gradient 90:10 → 05:95) of purifying.We obtain the target compound of 2.26 grams (theoretical value 68%).
LC-MS (method 10): R
t=1.23 min; MS (EIpos): m/z=340 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.06?(s,?3H),?2.25?(s,?3H),?3.74?(s,?3H),?6.26?(s,?1H),?6.84-6.88?(m,?1H)?7.23-7.29?(m,?3H),?7.43-7.52?(m,?2H),?7.84?(dd,?1H),?9.34?(s,?1H)。
Embodiment 146A
Methyl-2-{[4-bromo-1-(2-fluoro-6-aminomethyl phenyl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino } benzoic ether
With 2.233 grams (6.580 mmole) from the compound dissolution of embodiment 145A in 36 milliliters of methylene dichloride, and with in ice-cooled, portioning adds 0.941 and restrains (3.290 mmole) 1,3-two bromo-5,5-T10.Reaction test by HPLC shows to be finished after being reflected at 20 minutes.Add methylene dichloride, organic phase water, saturated sodium bicarbonate aqueous solution and the washing of 10% sodium thiosulfate solution.Organic phase is with after dried over sodium sulfate and concentrating in rotatory evaporator.We obtain the target compound of 2.599 grams (theoretical value 94%).
LC-MS (method 10): R
t=1.35 min; MS (EIpos): m/z=418 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.11?(s,?3H),?2.28?(s,?3H),?3.80?(s,?3H),?6.59?(d,?1H),?6.80-6.84?(m,?1H)?7.19-7.25?(m,?2H),?7.38-7.45?(m,?2H),?7.80?(dd,?1H),?9.05?(s,?1H)。
Embodiment 147A
Methyl-2-{[4-(8-fluorine quinoxalin-6-yl)-1-(2-fluoro-6-aminomethyl phenyl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino } benzoic ether
54 milligrams of (0.060 mmoles) three-(dibenzylidene-acetone)-two palladium (0) and 40 milligrams of (0.143 mmole) tricyclohexyl phosphines are added in 1092 milligrams of crude products from embodiment 91A.It is found time 5 times and ventilate with argon gas.Add 3 milliliters of dioxanes, 500 milligrams (1.195 mmole) compound and 1.60 milliliter of 1.27 M potassiumphosphate aqueous solution subsequently from embodiment 146A.It was stirred 5 hours down at 100 ℃.After cooling, add entry and it is used ethyl acetate extraction.The organic phase that merges concentrates through dried over sodium sulfate and in rotatory evaporator.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 317 milligrams (45% of theoretical values, according to HPLC, purity 83%).
LC-MS (method 10): R
t=1.21 min; MS (EIpos): m/z=486 [M+H]
+
Application examples:
Embodiment 1
2-{[4-(quinoxalin-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-fluorobenzoic acid
Be dissolved in 10 milligrams of (0.021 mmole) embodiment 2A in 1.25 milliliters of dioxane/water (4/1) and add 43 microlitres (0.043 mmole) 2M sodium hydroxide solution.It is at room temperature reacted whole night.Record after reaction finishes by analyzing HPLC, remove volatile constituent by underpressure distillation.Residue is dissolved in 20 ml waters and with in the saturated hydrochloric acid aqueous ammonium with gained solution.It uses 20 milliliters of ethyl acetate extractions (2x) subsequently.The organic phase that merges is with after dried over mgso.In rotatory evaporator, remove desolvate and product dry under high vacuum at last.Thus, we obtain the target compound of 9.0 milligrams (theoretical values 88%).
LC-MS (method 3): R
t=1.89 min; MS (EIpos): m/z=454 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.17?(s,?3H),?2.48?(s,?3H),?6.47?(dd,?1H),?7.03?(mc,?1H),?7.24?(m,?1H).?7.31-7.34?(m,?2H),?7.37?(dd,?1H),?7.39?(d,?1H),?7.97?(dd,?1H),?8.05?(d,?1H),?8.10?(d,?1H),?8.89?(d,?1H),?8.90?(d,?1H),?9.37?(sbr,?1H),?13.39?(sbr,?1H)。
Embodiment 2
2-{[4-(quinoxalin-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-chloro-benzoic acid
Be dissolved in 57 milligrams of (0.118 mmole) embodiment 3A in 2.5 milliliters of dioxane/water (4/1) and add 236 microlitres (0.236 mmole) 1M sodium hydroxide solution.It is at room temperature reacted whole night.Record after reaction finishes by analyzing HPLC, remove volatile constituent by underpressure distillation.Residue is dissolved in 20 ml waters and with in the saturated hydrochloric acid aqueous ammonium with gained solution.It uses 20 milliliters of ethyl acetate extractions (2x) subsequently.The organic phase that merges is with after dried over mgso.In rotatory evaporator, remove desolvate and product dry under high vacuum at last.Thus, we obtain the target compound of 45 milligrams (theoretical values 81%).
LC-MS (method 1): R
t=2.45 min; MS (EIpos): m/z=470 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.17?(s,?3H),?2.47?(s,?3H),?6.36?(d,?1H),?6.93?(d,?1H),?7.24?(m,?1H).?7.28-7.40?(m,?3H),?7.64?(sbr,?1H),?7.93?(d,?1H),?8.00?(d,?1H),?8.06?(d,?1H),?8.87?(d,?1H),?8.89?(d,?1H)。
Embodiment 3
2-{[4-(quinoxalin-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-tolyl acid
Be dissolved in 18 milligrams of (0.038 mmole) embodiment 4A in 1.25 milliliters of dioxane/water (4/1) and add 75 microlitres (0.075 mmole) 1M sodium hydroxide solution.It is at room temperature reacted whole night.Record after reaction finishes by analyzing HPLC, remove volatile constituent by underpressure distillation.Residue is dissolved in 20 ml waters and with in the saturated hydrochloric acid aqueous ammonium with gained solution.It uses 20 milliliters of ethyl acetate extractions (2x) subsequently.The organic phase that merges is with after dried over mgso.In rotatory evaporator, remove desolvate and product dry under high vacuum at last.Thus, we obtain the target compound of 10 milligrams (theoretical values 59%).
LC-MS (method 2): R
t=2.19 min; MS (EIpos): m/z=450 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.03?(s,?3H),?2.16?(s,?3H),?2.48?(s,?3H),?6.37?(d,?1H),?6.94?(m,?1H),?7.23?(m,?1H),?7.30-7.34?(m,?2H),?7.37?(d,?1H),?7.47?(d,?1H),?7.96?(dd,?1H),?8.03?(d,?1H),?8.09?(d,?1H),?8.88?(d,?1H),?8.90?(d,?1H),?12.97?(s,?1H)。
Embodiment 4
2-{[4-(quinoxalin-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-phenylformic acid
Be dissolved in 27 milligrams of (0.060 mmole) embodiment 5A in 1.5 milliliters of dioxane/water (4/1) and add 120 microlitres (0.120 mmole) 1M sodium hydroxide solution.It is at room temperature reacted whole night.Record after reaction finishes by analyzing HPLC, remove volatile constituent by underpressure distillation.Residue is dissolved in 20 ml waters and with in the saturated hydrochloric acid aqueous ammonium with gained solution.It uses 20 milliliters of ethyl acetate extractions (2x) subsequently.The organic phase that merges is with after dried over mgso.The gained crude product passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).This produces the target compound of 15 milligrams (theoretical values 57%).
LC-MS (method 1): R
t=2.21 min; MS (EIpos): m/z=436 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.17?(s,?3H),?2.48?(s,?3H),?6.46?(d,?1H),?6.57?(t,?1H),?7.10?(mc,?1H),?7.24?(mc,?1H),?7.29-7-35?(m,?2H),?7.40?(d,?1H),?7.66?(dd,?1H),?7.97?(dd,?1H),?8.04?(d,?1H),?8.10?(d,?1H),?8.88?(d,?1H),?8.89?(d,?1H),?9.58?(sbr,?1H),?13.04?(sbr,?1H)。
Embodiment 5
2-{[4-(quinoxalin-6-yl)-1-(2-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid
Be dissolved in 50 milligrams of (0.100 mmole) embodiment 8A in 4.0 milliliters of dioxane/water (4/1) and add 200 microlitres (0.200 mmole) 1M sodium hydroxide solution.It is at room temperature reacted whole night.Record after reaction finishes by analyzing HPLC, remove volatile constituent by underpressure distillation.Residue is dissolved in 20 ml waters and with in the 1N hydrochloric acid and gained solution.It uses 20 milliliters of ethyl acetate extractions (2x) subsequently.The organic phase that merges is with after dried over mgso.Products therefrom is dry under high vacuum.This produces the target compound of 48 milligrams (theoretical values 99%).
LC-MS (method 1): R
t=2.20 min; MS (EIpos): m/z=486 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.48?(s,?3H),?3.55?(s,?3H),?6.46?(d,?1H),?6.77?(dd,?1H),?7.15?(d,?1H),?7.41-7.58?(m,?2H),?7.60-7.67?(mc,?2H),?7.93?(dd,?1H),?8.04?(d,?1H),?8.07?(d,?1H),?8.89?(d,?1H),?8.90?(d,?1H),?9.31?(sbr,?1H),?13.20?(sbr,?1H)。
Embodiment 6
2-{[4-(quinoxalin-6-yl)-1-(2-aminomethyl phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] amino }-the 5-chloro-benzoic acid
138 milligrams of (0.209 mmole) embodiment 11A and 1.58 gram (7.51 mmole) quinoxalin-6-yl borate hydrochlorates are dissolved among 1.5 milliliters of DMF.After adding 0.420 milliliter of (8.00 mmole) 2M aqueous sodium carbonate, it is used argon-degassed.Add 21.7 milligrams of (0.019 mmoles) four (triphenyl phosphine) palladiums (0).Kept 4 hours down at 110 ℃ subsequently.By checking with LC-MS, except that the expection methyl esters, we have detected the respective acids of remarkable ratio.On diatomite, filter this mixture.It is washed with methylene dichloride again, and in rotatory evaporator concentrated filtrate.Organic phase is removed through dried over sodium sulfate and in rotatory evaporator and is desolvated.The gained crude product passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).This produces the target compound of 50 milligrams (theoretical values 46%).
LC-MS (method 1): R
t=2.79 min; MS (EIpos): m/z=524 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.19?(s,?3H),?6.58?(d,?1H),?7.18?(dd,?1H),?7.30?(mc,?1H),?7.36-7.43?(m,?2H),?7.52-7.59?(m,?2H),?7.93?(dd,?1H),?8.12?(d,?1H),?8.19?(d,?1H),?8.94-8.96?(mc,?2H),?9.57?(sbr,?1H),?13.47(sbr,?1H)。
Embodiment 7
2-{[4-(quinoxalin-6-yl)-1-(2-ethylphenyl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid
With 225 milligrams (0.456 mmoles) from the compound dissolution of embodiment 15A at 20 milliliters of dioxane/water (among the v/v=3:1) and add 685 microlitre 1N sodium hydroxide solutions.With its stirred overnight at room temperature.This mixture is with the 1N hcl acidifying and use ethyl acetate extraction.The organic phase that merges is washed with saturated sodium-chloride water solution, concentrates through dried over sodium sulfate and in rotatory evaporator.This residue is dry under high vacuum.We obtain the target compound of 220 milligrams (theoretical values 100%).
LC-MS (method 3): R
t=1.93 min; MS (EIpos): m/z=480 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?1.07?(t,?3H),?2.47?(q,?2H),?2.48?(s,?3H),?3.55?(s,?3H),?6.45?(d,?1H),?6.76?(dd,?1H),?7.15?(d,?1H),?7.23-7.28?(m,?1H),?7.35?(d,?1H),?7.39?(d,?2H),?7.96?(dd,?1H),?8.02?(d,?1H),?8.09?(d,?1H),?8.88?(d,?1H),?8.89?(d,?1H),?9.23?(sbr,?1H),?13.15?(sbr,?1H)。
Embodiment 8
5-methoxyl group-2-{[3-methyl isophthalic acid-(2-aminomethyl phenyl)-4-(pyrido [2,3-b] pyrazine-7-yl)-1H-pyrazoles-5-yl] amino } phenylformic acid
With 57 milligrams (0.119 mmoles) from the compound dissolution of embodiment 20A at 5 milliliters of dioxane/water (among the v/v=3:1) and add 180 microlitre 1N sodium hydroxide solutions.With its stirred overnight at room temperature.This reaction mixture is with the 1N hcl acidifying and use ethyl acetate extraction.The organic phase that merges is washed with saturated sodium-chloride water solution, concentrates through dried over sodium sulfate and in rotatory evaporator.This residue is dry under high vacuum.We obtain the target compound of 50 milligrams (theoretical values 90%).
LC-MS (method 1): R
t=2.00 min; MS (EIpos): m/z=467 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.18?(s,?3H),?2.50?(s,?3H),?3.55?(s,?3H),?6.44?(d,?1H),?6.78?(dd,?1H),?7.16?(d,?1H),?7.23-7.29?(m,?1H),?7.32-7.35?(m,?2H),?7.39?(d,?1H),?8.51?(d,?1H),?9.02?(d,?1H),?9.07?(d,?1H),?9.25?(sbr,?1H),?9.26?(d,?1H),?13.18?(sbr,?1H)。
Embodiment 9
2-{[4-(1H-indazole-5-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid
With 16 milligrams (0.034 mmoles) from the compound dissolution of embodiment 21A at 1.25 milliliters of dioxane/water (among the v/v=3:1) and add 50 microlitre 1N sodium hydroxide solutions.With its stirred overnight at room temperature.This reaction mixture is with the 1N hcl acidifying and use ethyl acetate extraction.The organic phase that merges is washed with saturated sodium-chloride water solution, concentrates through dried over sodium sulfate and in rotatory evaporator.This residue is dry under high vacuum.We obtain the target compound of 50 milligrams (theoretical values 90%).
LC-MS (method 1): R
t=2.13 min; MS (EIpos): m/z=4454 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.14?(s,?3H),?2.36?(s,?3H),?3.56?(s,?3H),?6.40?(d,?1H),?6.77?(dd,?1H),?7.13?(d,?1H),?7.19-7.24?(m,?1H),?7.27-7.33?(m,?3H),?7.37?(dd,?1H),?7.46?(d,?1H),?7.75?(s,?1H),?8.10?(s,?1H),?9.09?(sbr,?1H)?13.02?(sbr,?1H),?13.06?(sbr,?1H)。
Embodiment 10
2-{[4-(quinoline-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid
With 70 milligrams (0.146 mmoles) from the compound dissolution of embodiment 22A at 5 milliliters of dioxane/water (among the v/v=3:1) and add 220 microlitre 1N sodium hydroxide solutions.With its stirred overnight at room temperature.This reaction mixture is with the 1N hcl acidifying and use ethyl acetate extraction.The organic phase that merges is washed with saturated sodium-chloride water solution, concentrates through dried over sodium sulfate and in rotatory evaporator.This residue is dry under high vacuum.We obtain the target compound of 69 milligrams (theoretical values 100%).
LC-MS (method 3): R
t=1.60 min; MS (EIpos): m/z=465 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.15?(s,?3H),?2.46?(s,?3H),?3.55?(s,?3H),?6.40?(d,?1H),?6.76?(dd,?1H),?7.14?(s,?1H),?7.22-7.27?(m,?1H),?7.30-7.39?(m,?3H),?7.66?(dd,?1H),?7.93?(dd,?1H),?8.00?(d,?1H),?8.10?(s,?1H),?8.49?(d,?1H),?8.95?(dd,?1H),?9.19?(s,?1H),?13.14?(sbr,?1H)。
Embodiment 11
2-{[4-(1,3-benzothiazole-5-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid
With 55 milligrams (0.114 mmoles) from the compound dissolution of embodiment 23A at 2.7 milliliters of dioxane/water (among the v/v=3:1) and add 170 microlitre 1N sodium hydroxide solutions.With its stirred overnight at room temperature.This reaction mixture is with the 1N hcl acidifying and use ethyl acetate extraction.The organic phase that merges is washed with saturated sodium-chloride water solution, concentrates through dried over sodium sulfate and in rotatory evaporator.This residue is dry under high vacuum.We obtain the target compound of 51 milligrams (theoretical values 95%).
LC-MS (method 4): R
t=1.23 min; MS (EIpos): m/z=471 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.15?(s,?3H),?2.41?(s,?3H),?3.57?(s,?3H),?6.41?(d,?1H),?6.81?(dd,?1H),?7.14?(d,?1H),?7.20-7.25?(m,?1H),?7.29-7.32?(m,?2H),?7.35?(d,?1H),?7.54?(dd,?1H),?8.10?(s,?1H),?8.11?(d,?1H),?8.10?(s,?1H),?8.11?(d,?1H),?9.12?(sbr,?1H),?9.36?(s,?1H),?13.08?(sbr,?1H)。
Embodiment 12
5-methoxyl group-2-{[3-methyl isophthalic acid-(2-aminomethyl phenyl)-4-(naphthalene-2-yl)-1H-pyrazoles-5-yl] amino } phenylformic acid
With 23 milligrams (0.048 mmoles) from the compound dissolution of embodiment 24A at 2.2 milliliters of dioxane/water (among the v/v=3:1) and add 70 microlitre 1N sodium hydroxide solutions.With its stirred overnight at room temperature.This reaction mixture is with the 1N hcl acidifying and use ethyl acetate extraction.The organic phase that merges is washed with saturated sodium-chloride water solution, concentrates through dried over sodium sulfate and in rotatory evaporator.This residue is dry under high vacuum.We obtain the target compound of 28 milligrams (theoretical values 100%).
LC-MS (method 2): R
t=2.51 min; MS (EIpos): m/z=464 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.16?(s,?3H),?2.44?(s,?3H),?3.55?(s,?3H),?6.41?(d,?1H),?6.78?(dd,?1H),?7.14?(d,?1H),?7.22-7.26?(m,?1H),?7.29-7.34?(m,?2H),?7.36?(d,?1H),?7.44-7.50?(m,?2H),?7.57?(dd,?1H),?7.81-7.86?(m,?3H),?7.93?(s,?1H),?9.15?(sbr,?1H),?13.10?(sbr,?1H)。
Embodiment 13
2-{[4-(quinoxalin-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-ethyl benzoate
With 80 milligrams (0.168 mmoles) from the compound dissolution of embodiment 18A at 8 milliliters of dioxane/water (among the v/v=3:1) and add 250 microlitre 1N sodium hydroxide solutions.With its stirred overnight at room temperature.Add again 250 microlitre 1N sodium hydroxide solutions and with this mixture 40 ℃ of following stirred overnight.This reaction mixture is with the 1N hcl acidifying and use ethyl acetate extraction.The organic phase that merges is washed with saturated sodium-chloride water solution, concentrates through dried over sodium sulfate and in rotatory evaporator.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 58 milligrams (theoretical values 74%).
LC-MS (method 3): R
t=2.06 min; MS (EIpos): m/z=464 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?0.97?(t,?3H),?2.17?(s,?3H),?2.34?(q,?2H),?2.48?(s,?3H),?6.39?(d,?1H),?6.97?(dd,?1H),?7.22-7.27?(m,?1H),?7.30-7.34?(m,?2H),?7.39?(d,?1H),?7.49?(d,?1H),?7.97?(dd,?1H),?8.04?(d,?1H),?8.10?(d,?1H),?8.88?(d,?1H),?8.89?(d,?1H),?9.43?(s,?1H),?12.99?(sbr,?1H)。
Embodiment 14
2-{[4-(quinoxalin-6-yl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid
Add 845 microlitre 1N aqueous sodium hydroxide solutions in 8 milliliters of dioxane/water (3:1) 200 milligrams (0.42 mmoles) from methyl-2-{[4-(quinoxalin-6-yl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl of embodiment 27A] amino } in the benzoic ether.At room temperature after the stirred overnight, this reaction mixture separates (method 8) with the acidifying of 1N aqueous hydrochloric acid and by preparation HPLC.Behind evaporation concentration product cut, obtain the target compound of 163 milligrams (theoretical values 92%).
LC-MS (method 4): R
t=1.15 min; MS (EIpos): m/z=422 [M+H]
+
1H?NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.14?(s,?3H),?6.43?(d,?1H),?6.67?(t,?1H),?7.19?(td,?1H),?7.20?-?7.29?(m,?1H),?7.34?(d,?2H),?7.41?(d,?1H),?7.77?(dd,?1H),?8.05?(d,?1H),?8.19?(dd,?1H),?8.25?(s,?1H),?8.52?(s,?1H),?8.85?(AB-System,?2H),?9.63?(sbr,?1H),?13.13?(sbr,?1H)。
Embodiment 15
2-{[4-(quinoxalin-6-yl)-1-phenyl-1H-pyrazoles-5-yl] amino } phenylformic acid
After reacting as in Example 17, handle and purifying, with 90 milligrams (0.21 mmoles) methyl-2-{[4-(quinoxalin-6-yl)-1-phenyl-1H-pyrazoles-5-yl from embodiment 29A] amino }-benzoic ether is that raw material obtains the target compound of 80 milligrams (theoretical values 92%).
LC-MS (method 3): R
t=1.78 min; MS (EIpos): m/z=408 [M+H]
+
1H?NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?6.29?(d,?1H),?6.67?(t,?1H),?7.16?(td,?1H),?7.35?(t,?1H),?7.44?(t,?2H),?7.64?(d,?2H),?7.83?(dd,?1H),?8.05?(d,?1H),?8.20?(dd,?1H),?8.27?(s,?1H),?8.53?(s,?1H),?8.85?(AB-System,?2H),?9.77?(sbr,?1H),?13.25?(sbr,?1H)。
Embodiment 16
2-{[4-(7-fluorine quinoxalin-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid
With 164 milligrams (about 0.132 mmoles) from the compound dissolution of embodiment 32A at 2000 microlitre dioxane/water (among the v/v=3:1) and add 200 microlitre 1N sodium hydroxide solutions.With its stirred overnight at room temperature.This reaction mixture is with the 1N hcl acidifying and use ethyl acetate extraction.The organic phase that merges is washed with saturated sodium-chloride water solution, concentrates through dried over sodium sulfate and in rotatory evaporator.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 39 milligrams (theoretical values 61%).
LC-MS (method 3): R
t=2.29 min; MS (EIpos): m/z=484 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.18?(s,?3H),?2.31?(s,?3H),?3.52?(s,?3H),?6.45?(d,?1H),?6.74?(dd,?1H),?7.08?(d,?1H),?7.23-7.36?(m,?3H),?7.39?(d,?1H),?7.90?(d,?1H),?8.15?(d,?1H),?8.90-8.93?(m,?2H)?9.16?(sbr,?1H),?13.12?(sbr,?1H)。
Embodiment 17
2-{[4-(7-chloro-quinoxaline-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid
With 36 milligrams (about 0.069 mmoles) from the compound dissolution of embodiment 37A at 3000 microlitre dioxane/water (among the v/v=3:1) and add 100 microlitre 1N sodium hydroxide solutions.With its stirred overnight at room temperature.This reaction mixture is with the 1N hcl acidifying and use ethyl acetate extraction.The organic phase that merges is washed with saturated sodium-chloride water solution, concentrates through dried over sodium sulfate and in rotatory evaporator.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 26 milligrams (theoretical values 74%).
LC-MS (method 4): R
t=1.22 min; MS (EIpos): m/z=500 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.19?(s,?3H),?2.23?(s,?3H),?3.50?(s,?3H),?6.53?(d,?1H),?6.72?(dd,?1H),?7.04?(d,?1H),?7.24-7.29?(m,?1h),?7.32-7.38?(m,?3H),?8.18?(s,?1H),?8.24?(s,?1H),?8.95?(s,?2H),?9.10?(sbr,?1H),?13.08?(sbr,?1H)。
Embodiment 18
5-methoxyl group-2-{[3-methyl-4-(7-methyl-quinoxaline-6-yl)-1-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid
With 138 milligrams (purity 88%, 0.280 mmoles) from the compound dissolution of embodiment 42A at 4000 microlitre dioxane/water (among the v/v=3:1) and add 370 microlitre 1N sodium hydroxide solutions.With its stirred overnight at room temperature.This reaction mixture is with the 1N hcl acidifying and use ethyl acetate extraction.The organic phase that merges is washed with saturated sodium-chloride water solution, concentrates through dried over sodium sulfate and in rotatory evaporator.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 96 milligrams (theoretical values 81%).
LC-MS (method 3): R
t=1.84 min; MS (EIpos): m/z=480 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.18?(s,?3H),?2.19?(s,?3H),?2.43?(s,?3H),?3.51?(s,?3H),?6.54?(d,?1H),?6.75?(dd,?1H),?7.04?(d,?1H),?7.24-7.29?(m,?1h),?7.31-7.39?(m,?3H),?7.93?(s,?1H),?7.98?(s,?1H),?8.85?(d,?1H),?8.87?(d,?1H),?9.02?(sbr,?1H),?13.08?(sbr,?1H)。
Embodiment 19
2-{[4-(5-chloro-quinoxaline-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid
With 172 milligrams (about 0.167 mmoles) from the compound dissolution of embodiment 47A at 2500 microlitre dioxane/water (among the v/v=3:1) and add 250 microlitre 1N sodium hydroxide solutions.With its stirred overnight at room temperature.This reaction mixture is with the 1N hcl acidifying and use ethyl acetate extraction.The organic phase that merges is washed with saturated sodium-chloride water solution, concentrates through dried over sodium sulfate and in rotatory evaporator.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 66 milligrams (theoretical values 79%).
LC-MS (method 3): R
t=1.87 min; MS (EIpos): m/z=500 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.19?(s,?3H),?2.23?(s,?3H),?3.48?(s,?3H),?6.49?(d,?1H),?6.68?(dd,?1H),?7.03?(d,?1H),?7.25-7.30?(m,?1h),?7.32-7.39?(m,?3H),?7.91?(d,?1H),?8.03?(d,?1H),?9.01?(d,?1H),?9.04?(d,?2H),?9.12?(sbr,?1H),?13.09?(sbr,?1H)。
Embodiment 20
5-methoxyl group-2-{[3-methyl isophthalic acid-(2-aminomethyl phenyl)-4-([1,2,4] triazolo [1,5-a] pyridine-6-yl)-1H-pyrazoles-5-yl] amino } phenylformic acid
With 152 milligrams (0.324 mmoles) from the compound dissolution of embodiment 50A at 4.8 milliliters of dioxane/water (among the v/v=3:1) and add 0.8 milliliter of 1N sodium hydroxide solution.With its stirred overnight at room temperature.This reaction mixture is with the 1N hcl acidifying and use ethyl acetate extraction.The organic phase that merges is washed with saturated sodium-chloride water solution, concentrates through dried over sodium sulfate and in rotatory evaporator.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 116 milligrams (theoretical values 79%).
LC-MS (method 3): R
t=1.05 min; MS (EIpos): m/z=455 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.15?(s,?3H),?2.41?(s,?3H),?3.57?(s,?3H),?6.41?(d,?1H),?6.81?(dd,?1H),?7.15?(d,?1H),?7.21-7.26?(m,?1H),?7.29-7.33?(m,?3H),?7.73?(dd,?1H),?7.81?(d,?1H),?8.47?(s,?1H),?9.00?(s,?1H),?9.11?(sbr,?1H),?13.10?(sbr,?1H)。
Embodiment 21
2-{[4-(quinoxalin-6-yl)-1-(2-p-methoxy-phenyl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid
With 60 milligrams (0.121 mmoles) from the compound dissolution of embodiment 54A at 1.8 milliliters of dioxane/water (among the v/v=3:1) and add 180 microlitre 1N sodium hydroxide solutions.With its stirred overnight at room temperature.This mixture is with the 1N hcl acidifying and use ethyl acetate extraction.The organic phase that merges is washed with saturated sodium-chloride water solution, concentrates through dried over sodium sulfate and in rotatory evaporator.This residue is dry under high vacuum.We obtain the target compound of 57 milligrams (theoretical values 97%).
LC-MS (method 1): R
t=2.13 min; MS (EIpos): m/z=482 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.46?(s,?3H),?3.52?(s,?3H),?3.86?(s,?3H),?6.40?(d,?1H),?6.68?(dd,?1H),?7.03?(t,?1H),?7.15?(d,?1H),?7.20?(d,?1H),?7.39-7.44?(m,?2H),?7.91?(dd,?1H),?8.00?(d,?1H),?8.04?(d,?1H),?8.87?(d,?1H),?8.89?(d,?1H)?9.37?(sbr,?1H),?13.22?(sbr,?1H)。
Embodiment 22
2-{[4-(quinoxalin-6-yl)-1-(2-ethoxyl phenenyl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino }-the 5-methoxybenzoic acid
With 125 milligrams (0.343 mmoles) from the compound dissolution of embodiment 58A at 5 milliliters of dioxane/water (among the v/v=3:1) and add 515 microlitre 1N sodium hydroxide solutions.With its stirred overnight at room temperature.This mixture is with the 1N hcl acidifying and use ethyl acetate extraction.The organic phase that merges is washed with saturated sodium-chloride water solution, concentrates through dried over sodium sulfate and in rotatory evaporator.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 25 milligrams (theoretical values 15%).
LC-MS (method 4): R
t=1.14 min; MS (EIpos): m/z=496 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?1.38(t,?3H),?2.47?(s,?3H),?3.50?(s,?3H),?6.37?(d,?1H),?6.66?(dd,?1H),?7.02?(dt,?1H),?7.14?(d,?1H),?7.19?(d,?1H),?7.38-7.42?(m,?2H),?7.90?(dd,?1H),?8.01?(d,?1H),?8.03?(d,?1H),?8.87?(d,?1H),?8.88?(d,?1H)?9.39?(sbr,?1H),?13.22?(sbr,?1H)。
Embodiment 23
2-{[4-(quinoxalin-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-5-(difluoro-methoxy) phenylformic acid
With 57 milligrams (0.111 mmoles) from the compound dissolution of embodiment 61A in 2.2 milliliters of dioxane/water (v/v=10/1) and add 1.11 milliliters of (1.11 mmole) 1N sodium hydroxide solutions.It is at room temperature reacted whole night.In rotatory evaporator, remove as far as possible and desolvate.It is subsequently with the 1N hcl acidifying and use ethyl acetate extraction.The organic phase that merges concentrates through dried over mgso and in rotatory evaporator.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 50 milligrams (theoretical values 90%).
LC-MS (method 10): R
t=1.07 min; MS (EIpos): m/z=502 [M]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.18?(s,?3H),?2.48?(s,?3H),?6.49?(d,?1H),?6.94?(t,?1H),?7.00?(dd,?1H),?7.24?(m,?1H),?7.29-7.35?(m,?2H),?7.38-7.43?(m,?2H),?7.98?(dd,?1H),?8.05?(d,?1H),?8.11?(d,?1H),?8.89?(d,?1H),?8.90?(d,?1H),?9.48?(sbr,?1H),?13.40?(sbr,?1H)。
Embodiment 24
2-{[4-(8-fluoro-7-methoxyl group quinoxalin-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino }-phenylformic acid
Be dissolved in 160 milligrams of (about 0.161 mmole) embodiment 70A in 8 milliliters of dioxane/water (v/v=3/1) and add 0.804 milliliter of (0.804 mmole) 1N sodium hydroxide solution.It is at room temperature reacted whole night.With this mixture evaporation concentration and be dissolved in the water.It also uses ethyl acetate extraction (2x20 milliliter) with the 1N hcl acidifying subsequently.The organic phase that merges concentrates through dried over mgso and in rotatory evaporator.Residue is by preparation MPLC purification (Puriflash Analogix:40S: isohexane/ethyl acetate=98/2 → 10/90).We obtain the target compound of 25 milligrams (theoretical values 30%).
LC-MS (method 4): R
t=1.20 min; MS (EIpos): m/z=484 [M]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.20?(s,?3H),?2.28?(s,?3H),?4.01?(s,?3H),?6.48?(d,?1H),?6.53?(t,?1H),?7.10?(t,?1H),?7.24?(m,?1H),?7.27-7.35?(m,?2H),?7.39?(d,?1H),?7.58?(dd,?1H),?7.89?(d,?1H),?8.89?(d,?1H),?8.91?(d,?1H),?9.48?(sbr,?1H),?12.99?(sbr,?1H)。
Embodiment 25
2-{[4-(8-fluoro-7-methoxyl group quinoxalin-6-yl)-3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl] amino } phenylformic acid
Be dissolved in 160 milligrams of (about 0.199 mmole) embodiment 73A in 8 milliliters of dioxane/water (v/v=3/1) and add 0.827 milliliter of (0.827 mmole) 1N sodium hydroxide solution.It is at room temperature reacted whole night.With this mixture evaporation concentration and be dissolved in the water.It also uses ethyl acetate extraction (2x20 milliliter) with the 1N hcl acidifying subsequently.The organic phase that merges concentrates through dried over mgso and in rotatory evaporator.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 50 milligrams (theoretical values 54%).
LC-MS (method 4): R
t=1.20 min; MS (EIpos): m/z=470 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.28?(s,?3H),?4.03?(s,?1.5?H),?4.04?(s,?1.5?H),?6.34?(d,?1H),?6.56?(t,?1H),?7.11?(mc,?1H),?7.29?(t,?1H),?7.41?(t,?2H),?7.62-7.68?(m,?3H),?7.90?(d,?1H),?8.88?(d,?1H),?8.91?(d,?1H),?9.61?(sbr,?1H),?13.04?(sbr,?1H)。
Embodiment 26
2-{[4-(3-methoxyl group quinoxalin-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid
Be dissolved in 30 milligrams of (about 0.050 mmole) embodiment 75A in 5 milliliters of dioxanes and add 0.626 milliliter of (0.626 mmole) 1N sodium hydroxide solution.It is at room temperature reacted whole night, react whole night down at 80 ℃ subsequently.With this mixture evaporation concentration and be dissolved in the water.It also uses ethyl acetate extraction (2x20 milliliter) with the 1N hcl acidifying subsequently.The organic phase that merges concentrates through dried over mgso and in rotatory evaporator.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 5 milligrams (theoretical values 22%).
LC-MS (method 10): R
t=1.15 min; MS (EIpos): m/z=466 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.17?(s,?3H),?2.46?(s,?3H),?4.02?(s,?3?H),?6.44?(d,?1H),?6.56?(t,?1H),?7.11?(t,?1H),?7.23?(m,?1H),?7.27-7.35?(m,?2H),?7.37?(d,?1H),?7.65?(dd,?1H),?7.71?(dd,?1H),?7.88?(d,?1H),?7.92?(d,?1H),?8.52?(s,?1H),?9.60?(sbr,?1H)。
Embodiment 27
2-{[4-(quinoline-7-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid
Be dissolved in 37 milligrams of (0.082 mmole) embodiment 76A in 5 milliliters of dioxane/water (v/v=4/1) and add 0.206 milliliter of (0.206 mmole) 1N sodium hydroxide solution.It is at room temperature reacted whole night, react whole night down at 60 ℃ subsequently.With this mixture evaporation concentration and be dissolved in the water.It also uses ethyl acetate extraction (2x20 milliliter) with the 1N hcl acidifying subsequently.The organic phase that merges is through dried over mgso, and it is dry under high vacuum to concentrate volatile constituent and gained solid in rotatory evaporator.We obtain the target compound of 25 milligrams (theoretical values 70%).
LC-MS (method 2): R
t=1.93 min; MS (EIpos): m/z=435 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.17?(s,?3H),?2.47?(s,?3H),?6.46?(d,?1H),?6.57?(t,?1H),?7.12?(t,?1H),?7.23?(m,?1H),?7.28-7.35?(m,?2H),?7.39?(d,?1H),?7.50?(dd,?1H),?7.66?(dd,?1H),?7.72?(d,?1H),?7.94?(d,?1H),?8.04?(s,?1H),?8.33?(d,?1H),?8.87?(d,?1H),?9.53?(s,?1H),?13.02?(sbr,?1H)。
Embodiment 28
2-(4-[3-(dimethylamino) quinoxalin-6-yl]-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl } amino) phenylformic acid
Be dissolved in 79 milligrams of (0.160 mmole) embodiment 78A in 5 milliliters of dioxanes and add 1.604 milliliters of (1.604 mmole) 1N sodium hydroxide solutions.It was at room temperature reacted 72 hours.With this mixture evaporation concentration and be dissolved in the water.It also uses ethyl acetate extraction (2x20 milliliter) with the 1N hcl acidifying subsequently.The organic phase that merges concentrates through dried over mgso and in rotatory evaporator.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 72 milligrams (theoretical values 89%).
LC-MS (method 10): R
t=1.09 min; MS (EIpos): m/z=479 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.15?(s,?3H),?2.43?(s,?3H),?3.20?(s,?6H),?6.44?(d,?1H),?6.57?(t,?1H),?7.12?(t,?1H),?7.22?(mc,?1H),?7.27-7.33?(m,?2H),?7.36?(d,?1H),?7.42?(dd,?1H),?7.62?(d,?1H),?7.65?(d,?1H),?7.71?(d,?1H),?8.61?(s,?1H),?9.50?(sbr,?1H),?13.00?(sbr,?1H)。
Embodiment 29
2-{[4-(8-fluoro-7-hydroxy quinoxaline-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid
Be dissolved in 5 milligrams of (0.010 mmole) embodiment 82A in 0.6 milliliter of dioxane/water (v/v=5/1) and add 0.026 milliliter of (0.026 mmole) 1N sodium hydroxide solution.It is at room temperature reacted whole night, react whole night down at 60 ℃ subsequently.With this mixture evaporation concentration and be dissolved in the water.It also uses ethyl acetate extraction (2x20 milliliter) with the 1N hcl acidifying subsequently.The organic phase that merges is removed volatile constituent through dried over mgso and in rotatory evaporator.This residue is dry under high vacuum.We obtain the target compound of 4 milligrams (theoretical values 82%).
LC-MS (method 2): R
t=1.97 min; MS (EIpos): m/z=470 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.20?(s,?3H),?2.27?(s,?3H),?6.47-6.57?(m,?2H),?7.08?(t,?1H),?7.24?(mc,?1H),?7.27-7.34?(m,?2H),?7.38?(d,?1H),?7.58?(dd,?1H),?7.79?(d,?1H),?8.76?(d,?1H),?8.82?(d,?1H),?9.45?(sbr,?1H),?10.88?(sbr,?1H),?12.91?(sbr,?1H)。
Embodiment 30
2-{[4-(7-oxyethyl group-8-fluorine quinoxalin-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid
Be dissolved in 37 milligrams of (0.072 mmole) embodiment 84A in 4 milliliters of dioxane/water (v/v=3/1) and add 0.181 milliliter of (0.181 mmole) 1N sodium hydroxide solution.It is at room temperature reacted whole night, react whole night down at 60 ℃ subsequently.With this mixture evaporation concentration and be dissolved in the water.It also uses ethyl acetate extraction (2x20 milliliter) with the 1N hcl acidifying subsequently.The organic phase that merges is removed volatile constituent through dried over mgso and in rotatory evaporator.This residue is dry under high vacuum.We obtain the target compound of 31 milligrams (theoretical values 84%).
LC-MS (method 2): R
t=2.28 min; MS (EIpos): m/z=498 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?1.31?(t,?3H),?2.22?(s,?3H),?2.30?(s,?3H),?4.22?(q,?2H),?6.45?(d,?1H),?6.52?(t,?1H),?7.08?(t,?1H),?7.16-7.35?(m,?3H),?7.37?(d,?1H),?7.58?(d,?1H),?7.91?(s,?1H),?8.91?(d,?2H),?9.48?(s,?1H),?13.01?(sbr,?1H)。
Embodiment 31
2-(4-[8-fluoro-7-(2-hydroxyl-oxethyl) quinoxalin-6-yl]-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl } amino) phenylformic acid
Be dissolved in 40 milligrams of (0.070 mmole) embodiment 86A in 4 milliliters of dioxane/water (v/v=3/1) and add 0.351 milliliter of (0.351 mmole) 1N sodium hydroxide solution.It is at room temperature reacted whole night.With this mixture evaporation concentration and be dissolved in the water.It also uses ethyl acetate extraction (2x20 milliliter) with the 1N hcl acidifying subsequently.The organic phase that merges is removed volatile constituent through dried over mgso and in rotatory evaporator.This residue is dry under high vacuum.We obtain the target compound of 8.7 milligrams (theoretical values 24%).
LC-MS (method 2): R
t=1.99 min; MS (EIpos): m/z=514 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.22?(s,?3H),?2.30?(s,?3H),?3.68?(t,?2H),?4.17?(t,?2H),?6.38-6.60?(m,?2H),?7.07?(m,?1H),?7.23?(dt,?1H),?7.28-7.35?(m,?2H),?7.39?(d,?1H),?7.57?(dd,?1H),?7.89?(s,?1H),?8.89?(d,?1H),?8.91?(d,?1H),?9.44?(sbr,?1H),?12.96?(sbr,?1H)。
Embodiment 32
2-{[4-(4-methoxy quinoline-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid
Be dissolved in 99 milligrams of (0.207 mmole) embodiment 88A in 12.5 milliliters of dioxane/water (v/v=4/1) and add 0.517 milliliter of (0.517 mmole) 1N sodium hydroxide solution.It is at room temperature reacted whole night.With this mixture evaporation concentration and be dissolved in the water.It uses the 1N hcl acidifying and subsequently by this precipitated product of filtering separation.It washs with less water.This solid is dry under high vacuum at last.We obtain the target compound of 53 milligrams (theoretical values 55%).
LC-MS (method 2): R
t=1.73 min; MS (EIpos): m/z=465 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.17?(s,?3H),?2.45?(s,?3H),?4.06?(s,?3H),?6.44?(d,?1H),?6.58?(t,?1H),?7.11?(mc,?1H),?7.16?(d,?1H),?7.25?(mc,?1H),?7.29-7.35?(m,?2H),?7.40?(d,?1H),?7.68?(dd,?1H),?7.95?(s,?2H),?8.17?(s,?1H),?8.82?(d,?1H),?9.49?(s,?1H),?13.03?(sbr,?1H)。
Embodiment 33
2-{[4-(8-fluorine quinoxalin-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid
With 661 milligrams (1.174 mmoles) from the compound dissolution of embodiment 92A at 17 milliliters of dioxane/water (among the v/v=3:1) and add 2.9 milliliters of 1N sodium hydroxide solutions.With this mixture stirred overnight at room temperature.It uses the 1N hcl acidifying subsequently.With this mixture ethyl acetate extraction, the organic phase of merging is with the saturated sodium-chloride water solution washing and through dried over sodium sulfate.Organic phase concentrates in rotatory evaporator and residue is purified by preparing HPLC (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 269 milligrams (theoretical values 50%).
LC-MS (method 10): R
t=1.06 min; MS (EIpos): m/z=454 [M+H]+.
1H-NMR?(400?MHz,?DMSO-D6)：δ?[ppm]?=?2.18?(s,?3H),?6.45?(d,?1H),?6.59?(t,?1H),?7.10-7.15?(m,?1H),?7.22-7.27?(m,?1H),?7.30-7.34?(m,?2H),?7.40?(d,?1H),?7.68?(dd,?1H),?7.84?(dd,?1H),?7.96?(sbr,?1H),?8.92?(d,?1H),?8.97?(d,?1H),?9.56?(sbr,?1H),?13.06?(sbr,?1H)。
Embodiment 34
2-{[4-(8-fluorine quinoxalin-6-yl)-3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl] amino } phenylformic acid
With 284 milligrams (0.519 mmoles) from the compound dissolution of embodiment 93A at 8 milliliters of dioxane/water (among the v/v=3:1) and add 1.3 milliliters of 1N sodium hydroxide solutions.With this mixture stirred overnight at room temperature.It uses the 1N hcl acidifying subsequently.With this mixture ethyl acetate extraction, the organic phase of merging is with the saturated sodium-chloride water solution washing and through dried over sodium sulfate.Organic phase concentrates in rotatory evaporator and residue is purified by preparing HPLC (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 197 milligrams (theoretical values 86%).
LC-MS (method 10): R
t=1.05 min; MS (EIpos): m/z=440 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?6.30?(d,?1H),?6.60?(t,?1H),?7.09-7.14?(m,?1H),?7.31?(t,?1H),?7.43?(t,?2H),?7.64?(d,?1H),?7.73?(dd,?1H),?7.85?(dd,?1H),?7.97?(sbr,?1H),?8.93?(d,?1H),?8.98?(d,?1H),?9.71?(sbr,?1H),?13.09?(sbr,?1H)。
Embodiment 35
2-{[4-(7,8-difluoro quinoxalin-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid
With 150 milligrams (0.117 mmoles) from the compound dissolution of embodiment 99A at 4 milliliters of dioxane/water (among the v/v=3:1) and add 585 microlitre 1N sodium hydroxide solutions.With this mixture stirred overnight at room temperature.It uses the 1N hcl acidifying subsequently.With this mixture ethyl acetate extraction, the organic phase of merging is with the saturated nacl aqueous solution washing and through dried over sodium sulfate.Organic phase concentrates in rotatory evaporator and residue is purified by preparing HPLC (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 26 milligrams (theoretical values 45%).
LC-MS (method 4): R
t=1.25 min; MS (EIpos): m/z=472 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.20?(s,?3H),?2.34?(s,?3H),?6.48?(d,?1H),?6.55?(t,?1H),?7.07-7.12?(m,?1H),?7.24-7.29?(m,?1H),?7.31-7.36?(m,?2H),?7.41?(d,?1H),?7.61?(dd,?1H),?8.05?(dd,?1H),?8.98-9.00?(m,?2H),?9.54?(sbr,?1H),?13.06?(sbr,?1H)。
Embodiment 36
2-{[4-(7,8-difluoro quinoxalin-6-yl)-3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl] amino } phenylformic acid
With 148 milligrams (0.261 mmoles) from the compound dissolution of embodiment 100A at 4 milliliters of dioxane/water (among the v/v=3:1) and add 650 microlitre 1N sodium hydroxide solutions.With this mixture stirred overnight at room temperature.It uses the 1N hcl acidifying subsequently.With this mixture ethyl acetate extraction, the organic phase of merging is with the saturated sodium-chloride water solution washing and through dried over sodium sulfate.Organic phase concentrates in rotatory evaporator and residue is purified by preparing HPLC (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 69 milligrams (theoretical values 58%).
LC-MS (method 10): R
t=1.09 min; MS (EIpos): m/z=458 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.34?(s,?3H),?6.33?(d,?1H),?6.57?(t,?1H),?7.08-7.13?(m,?1H),?7.32?(t,?1H),?7.43?(t,?2H),?7.64-7.68?(m,?3H),?8.05?(dd,?1H),?8.99?(s,?2H),?9.72?(sbr,?1H),?13.09?(sbr,?1H)。
Embodiment 37
2-{[3-methyl isophthalic acid-(2-aminomethyl phenyl)-4-([1,2,4] triazolo [1,5-a] pyridine-7-yl)-1H-pyrazoles-5-yl] amino } phenylformic acid
With 148 milligrams (0.261 mmoles) from the compound dissolution of embodiment 104A at 3.2 milliliters of dioxane/water (among the v/v=3:1) and add 540 microlitre 1N sodium hydroxide solutions.With this mixture stirred overnight at room temperature.It uses the 1N hcl acidifying subsequently.With this mixture ethyl acetate extraction, the organic phase of merging is with the saturated sodium-chloride water solution washing and through dried over sodium sulfate.Organic phase concentrates in rotatory evaporator and residue is purified by preparing HPLC (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 57 milligrams (theoretical values 62%).
LC-MS (method 10): R
t=0.93 min; MS (EIpos): m/z=425 [M+H]+.
1H-NMR?(400?MHz,?DMSO-D6)：δ?[ppm]?=?2.15?(s,?3H),?2.47?(s,?3H),?6.44?(d,?1H),?6.61?(t,?1H),?7.13-7.17?(m,?1H),?7.21-7.25?(m,?1H),?7.28?(dd,?1H),?7.32?(d,?2H),?7.37?(d,?1H),?7.69?(dd,?1H),?7.84?(s,?1H),?8.43?(s,?1H),?8.87?(d,?1H),?9.54?(s,?1H),?13.06?(sbr,?1H)。
Embodiment 38
2-{[4-(2-amino [1,2,4] triazolo [1,5-a] pyridine-6-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid
With 40 milligrams (0.088 mmoles) from the compound dissolution of embodiment 108A at 1.5 milliliters of dioxane/water (among the v/v=3:1) and add 220 microlitre 1N sodium hydroxide solutions.With this mixture stirred overnight at room temperature.It uses the 1N hcl acidifying subsequently.With this mixture ethyl acetate extraction, the organic phase of merging is with the saturated sodium-chloride water solution washing and through dried over sodium sulfate.Organic phase concentrates in rotatory evaporator.We obtain the target compound of 40 milligrams (theoretical values 100%).
LC-MS (method 10): R
t=0.87 min; MS (EIpos): m/z=440 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.16?(s,?3H),?2.38?(s,?3H),?6.09?(sbr,?2H),?6.44?(d,?1H),?6.60?(t,?1H),?7.14-7.19?(m,?1H),?7.20-7.25?(m,?1H),?7.28-7.35?(m,?4H),?7.52?(dd,?1H),?7.67?(dd,?1H),?8.59?(s,?1H),?9.41?(s,?1H),?12.99?(sbr,?1H)。
Embodiment 39
2-{[4-(2-amino [1,2,4] triazolo [1,5-a] pyridine-7-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid
With 125 milligrams (0.276 mmoles) from the compound dissolution of embodiment 112A at 4 milliliters of dioxane/water (among the v/v=3:1) and add 690 microlitre 1N sodium hydroxide solutions.With this mixture stirred overnight at room temperature.It uses the 1N hcl acidifying subsequently.With this mixture ethyl acetate extraction, the organic phase of merging is with the saturated sodium-chloride water solution washing and through dried over sodium sulfate.Organic phase concentrates in rotatory evaporator and residue is purified by preparing HPLC (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 66 milligrams (theoretical values 54%).
LC-MS (method 4): R
t=0.99 min; MS (EIpos): m/z=440 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.14?(s,?3H),?2.43?(s,?3H),?5.93?(sbr,?2H),?6.43?(d,?1H),?6.62?(t,?1H),?6.92?(dd,?1H),?7.15-7.19?(m,?1H),?7.20-7.26?(m,?1H),?7.28-7.37?(m,?4H),?7.69?(dd,?1H),?8.44?(d,?1H),?9.48?(s,?1H),?13.04?(sbr,?1H)。
Embodiment 40
2-{[4-(1-aminoisoquinoline-7-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid
Be dissolved in 100 milligrams of (0.216 mmole) embodiment 113A in 7 milliliters of dioxanes and add 2.157 milliliters of (2.157 mmole) 1N sodium hydroxide solutions.Make its reaction whole night.With this mixture evaporation concentration and be dissolved in the water.It also uses ethyl acetate extraction (2x20 milliliter) with the 1N hcl acidifying subsequently.The organic phase that merges concentrates through dried over mgso and in rotatory evaporator.It is dry under high vacuum at last.We obtain the target compound of 64 milligrams (theoretical values 66%).
LC-MS (method 10): R
t=0.83 min; MS (EIpos): m/z=450 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.17?(s,?3H),?2.44?(s,?3H),?6.37?(d,?1H),?6.56?(t,?1H),?7.05?(d,?1H),?7.09?(t,?1H),?7.25?(mc,?1H),?7.28-7.39?(m,?3H),?7.62-7.71?(m,?2H),?7.78?(d,?1H),?7.84?(d,?1H),?8.23?(sbr,?2H),?8.46?(s,?1H),?9.56?(s,?1H)。
Embodiment 41
2-{[4-(8-fluorine quinoline-6-yl)-3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-yl] amino } phenylformic acid
Be dissolved in 43 milligrams of (0.095 mmole) embodiment 115A in 5 milliliters of dioxane/water (4/1) and add 38 milligrams of (0.950 mmole) sodium hydroxide.It is reacted whole night down at 80 ℃.With this mixture evaporation concentration and be dissolved in the water.It also uses ethyl acetate extraction (2x20 milliliter) with the 1N hcl acidifying subsequently.The organic phase that merges concentrates through dried over mgso and in rotatory evaporator.This residue passes through preparation HPLC purifies (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 17 milligrams (theoretical values 41%).
LC-MS (method 10): R
t=1.06 min; MS (EIpos): m/z=439 [M+H]+.
1H-NMR?(400?MHz,?DMSO-D6)：δ?[ppm]?=?2.48?(s,?3H),?6.28?(d,?1H),?6.59?(t,?1H),?7.11?(t,?1H),?7.31?(t,?1H),?7.43?(t,?2H),?7.56-7.77?(m,?5H),?7.86?(s,?1H),?8.34?(d,?1H),?8.89?(d,?1H),?9.68?(s,?1H),?13.11?(sbr,?1H)。
Embodiment 42
2-{[4-(4-methoxy quinoline-7-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid
Be dissolved in 120 milligrams of (0.251 mmole) embodiment 117A in 5 milliliters of dioxane/water (4/1) and add 25 milligrams of (0.627 mmole) sodium hydroxide.It is at room temperature reacted whole night.With this mixture evaporation concentration and be dissolved in the water.It also uses ethyl acetate extraction (2x20 milliliter) with the 1N hcl acidifying subsequently.The organic phase that merges concentrates through dried over mgso and in rotatory evaporator.We obtain the target compound of 87 milligrams (theoretical values 75%).
LC-MS (method 10): R
t=0.87 min; MS (EIpos): m/z=465 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.16?(s,?3H),?2.47?(s,?3H),?4.11?(s,?3H),?6.44?(d,?1H),?6.58?(t,?1H),?7.11?(t,?1H),?7.16?(sbr,?1H),?7.24?(m,?1H),?7.29-7.35?(m,?2H),?7.38?(d,?1H),?7.67?(d,?1H),?7.77?(d,?1H),?8.04?(s,?1H),?8.13?(d,?1H),?8.84?(sbr,?1H),?9.56?(s,?1H)。
Embodiment 43
2-{[4-(5-fluquinconazole quinoline-7-yl)-3-methyl isophthalic acid-(2-aminomethyl phenyl)-1H-pyrazoles-5-yl] amino } phenylformic acid
Be dissolved in 152 milligrams of (0.325 mmole) embodiment 119A in 5 milliliters of dioxanes and add 3.25 milliliters of (3.25 mmole) 1N sodium hydroxide solutions.It is at room temperature reacted whole night.With this mixture evaporation concentration and be dissolved in the water.It also uses ethyl acetate extraction (2x20 milliliter) with the 1N hcl acidifying subsequently.The organic phase that merges concentrates through dried over mgso and in rotatory evaporator.We obtain the target compound of 147 milligrams (theoretical values 99%).
LC-MS (method 10): R
t=1.05 min; MS (EIpos): m/z=454 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.17?(s,?3H),?3.17?(s,?3H),?6.43?(d,?1H),?6.59?(t,?1H),?7.13?(t,?1H),?7.25?(m,?1H),?7.29-7.36?(m,?2H),?7.40?(d,?1H),?7.64-7.76?(2xed,?2H),?7.90?(s,?1H),?9.31?(s,?1H),?9.58?(s,?1H),?9.63?(s,?1H),?13.08?(sbr,?1H)。
Embodiment 44
2-{[4-(8-fluorine quinoxalin-6-yl)-1-phenyl-3-(trifluoromethyl)-1H-pyrazoles-5-yl] amino } phenylformic acid
With 661 milligrams (1.174 mmoles) from the compound dissolution of embodiment 123A at 11 milliliters of dioxane/water (among the v/v=3:1) and add 1.53 milliliters of 1N sodium hydroxide solutions.With this mixture stirred overnight at room temperature.It uses the 1N hcl acidifying subsequently.With this mixture ethyl acetate extraction, the organic phase of merging is with the saturated sodium-chloride water solution washing and through dried over sodium sulfate.Organic phase concentrates in rotatory evaporator and residue is purified by preparing HPLC (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 108 milligrams (theoretical values 27%).
LC-MS (method 10): R
t=1.07 min; MS (EIpos): m/z=508 [M+H]+.
1H-NMR?(400?MHz,?DMSO-D6)：δ?[ppm]?=?2.49?(s,?3H),?6.47?(d,?1H),?6.59?(t,?1H),?7.10?(dt,?1H),?7.66-7.80?(m,?5H),?7.90-7.94?(m,?2H),?8.92?(d,?1H),?8.97?(dd,?1H),?9.64?(sbr,?1H),?13.13?(sbr,?1H)。
Embodiment 45
2-{[1-(2, the 5-3,5-dimethylphenyl)-4-(8-fluorine quinoxalin-6-yl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino } phenylformic acid
With 395 milligrams (0.821 mmoles) from the compound dissolution of embodiment 127A at 20 milliliters of dioxane/water (among the v/v=3:1) and add 1.64 milliliters of 1N sodium hydroxide solutions.With this mixture stirred overnight at room temperature.It uses the 1N hcl acidifying subsequently.With this mixture ethyl acetate extraction, the organic phase of merging is with the saturated sodium-chloride water solution washing and through dried over sodium sulfate.Organic phase concentrates in rotatory evaporator and residue is purified by preparing HPLC (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 164 milligrams (theoretical values 43%).
LC-MS (method 10): R
t=1.11 min; MS (EIpos): m/z=468 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.11?(s,?3H),?2.25?(s,?3H),?2.49?(s,?3H),?6.43?(d,?1H),?6.58?(t,?1H),?7.09-7.23?(m,?4H),?7.67?(dd,?1H),?7.84?(dd,?1H),?7.96?(s,?1H),?8.92?(d,?1H),?8.97?(dd,?1H),?9.57?(sbr,?1H),?13.09?(sbr,?1H)。
Embodiment 46
2-{[1-(2,4 difluorobenzene base)-4-(8-fluorine quinoxalin-6-yl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino } phenylformic acid
With 395 milligrams (0.821 mmoles) from the compound dissolution of embodiment 131A at 25 milliliters of dioxane/water (among the v/v=3:1) and add 1.85 milliliters of 1N sodium hydroxide solutions.With this mixture stirred overnight at room temperature.It uses the 1N hcl acidifying subsequently.With this mixture ethyl acetate extraction, the organic phase of merging is with the saturated sodium-chloride water solution washing and through dried over sodium sulfate.Organic phase concentrates in rotatory evaporator and residue is purified by preparing HPLC (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 219 milligrams (theoretical values 50%).
LC-MS (method 10): R
t=1.06 min; MS (EIpos): m/z=476 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.49?(s,?3H),?6.40?(d,?1H),?6.59-6.63?(m,?1H),?7.10-7.14?(m,?1H),?7.20-7.24?(m,?1H),?7.46-7.51?(m,?1H),?7.69-7.82?(m,?3H),?7.94(s,?1H),?8.93?(d,?1H),?8.98?(d,?1H),?9.64?(sbr,?1H),?13.14?(sbr,?1H)。
Embodiment 47
2-{[4-(8-fluorine quinoxalin-6-yl)-1-(3-fluoro-2-aminomethyl phenyl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino } phenylformic acid
With 277 milligrams (0.570 mmoles) from the compound dissolution of embodiment 135A at 15 milliliters of dioxane/water (among the v/v=3:1) and add 1.14 milliliters of 1N sodium hydroxide solutions.With this mixture stirred overnight at room temperature.It uses the 1N hcl acidifying subsequently.With this mixture ethyl acetate extraction, the organic phase of merging is with the saturated sodium-chloride water solution washing and through dried over sodium sulfate.Organic phase concentrates in rotatory evaporator and residue is purified by preparing HPLC (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 145 milligrams (theoretical values 54%).
LC-MS (method 10): R
t=1.08 min; MS (EIpos): m/z=472 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.10?(d,?3H),?6.42?(d,?1H),?6.80?(t,?1H),?7.11-7.15?(m,?1H),?7.23-7.31?(m,?3H),?7.68?(dd,?1H),?7.86?(dd,?1H),?7.98?(s,?1H),?8.93?(d,?1H),?8.98?(d,?1H),?9.58?(sbr,?1H),?13.10?(sbr,?1H)。
Embodiment 48
2-{[1-(2, the 5-difluorophenyl)-4-(8-fluorine quinoxalin-6-yl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino } phenylformic acid
With 390 milligrams (0.797 mmoles) from the compound dissolution of embodiment 139A at 20 milliliters of dioxane/water (among the v/v=3:1) and add 1.59 milliliters of 1N sodium hydroxide solutions.With this mixture stirred overnight at room temperature.It uses the 1N hcl acidifying subsequently.With this mixture ethyl acetate extraction, the organic phase of merging is with the saturated sodium-chloride water solution washing and through dried over sodium sulfate.Organic phase concentrates in rotatory evaporator and residue is purified by preparing HPLC (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 234 milligrams (theoretical values 62%).
LC-MS (method 10): R
t=1.07 min; MS (EIpos): m/z=476 [M+H]+.
1H-NMR?(400?MHz,?DMSO-D6)：δ?[ppm]?=?2.49?(s,?3H),?6.39?(d,?1H),?6.59-6.63?(m,?1H),?7.09-7.14?(m,?1H),?7.32-7.38?(m,?1H),?7.63-7.68?(m,?1H),?7.70?(dd,?1H),?7.81?(dd,?1H),?7.95?(s,?1H),?8.93?(d,?1H),?8.98?(d,?1H),?9.70?(sbr,?1H),?13.15?(sbr,?1H)。
Embodiment 49
2-{[4-(8-fluorine quinoxalin-6-yl)-1-(4-fluoro-2-aminomethyl phenyl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino } phenylformic acid
With 428 milligrams (0.882 mmoles) from the compound dissolution of embodiment 143A at 13 milliliters of dioxane/water (among the v/v=3:1) and add 1.76 milliliters of 1N sodium hydroxide solutions.With this mixture stirred overnight at room temperature.It uses the 1N hcl acidifying subsequently.With this mixture ethyl acetate extraction, the organic phase of merging is with the saturated sodium-chloride water solution washing and through dried over sodium sulfate.Organic phase concentrates in rotatory evaporator and residue is purified by preparing HPLC (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 194 milligrams (theoretical values 47%).
LC-MS (method 4): R
t=1.22 min; MS (EIpos): m/z=472 [M+H]
+
1H-NMR?(400?MHz,?DMSO-D
6)：δ?[ppm]?=?2.17?(s,?3H),?6.80?(dt,?1H),?7.07-7.15?(m,?2H),?7.21?(dd,?1H),?7.48?(dd,?1H),?7.69?(dd,?1H),?7.84?(dd,?1H),?7.96?(s,?1H),?8.92?(d,?1H),?8.98?(d,?1H),?9.55?(sbr,?1H),?13.08?(sbr,?1H)。
Embodiment 50
2-{[4-(8-fluorine quinoxalin-6-yl)-1-(2-fluoro-6-aminomethyl phenyl)-3-methyl isophthalic acid H-pyrazoles-5-yl] amino } phenylformic acid
With 316 milligrams (0.542 mmoles) from the compound dissolution of embodiment 147A at 13 milliliters of dioxane/water (among the v/v=3:1) and add 1.76 milliliters of 1N sodium hydroxide solutions.With this mixture stirred overnight at room temperature.It uses the 1N hcl acidifying subsequently.With this mixture ethyl acetate extraction, the organic phase of merging is with the saturated sodium-chloride water solution washing and through dried over sodium sulfate.Organic phase concentrates in rotatory evaporator and residue is purified by preparing HPLC (eluent: acetonitrile/water, gradient 10:90 → 90:10).We obtain the target compound of 101 milligrams (theoretical values 39%).
LC-MS (method 10): R
t=1.07 min; MS (EIpos): m/z=472 [M+H]+.
1H-NMR?(400?MHz,?DMSO-D6)：δ?[ppm]?=?2.15?(s,?3H),?2.48?(s,?3H),?6.26?(d,?1H),?6.71?(t,?1H),?7.19?(t,?2H),?7.38?(dt,?1H),?7.65-7.71?(m,?2H),?7.89?(s,?1H),?8.88?(d,?1H),?8.94?(d,?1H),?12.87?(sbr,?1H)。
B. the assessment of pharmacological efficacy
The pharmacotoxicological effect that can in following detection, show compound of the present invention:
Abbreviation:
| EDTA | Ethylenediamine tetraacetic acid (EDTA) |
| DMEM | Dulbecco improvement Eagle substratum |
| FCS | Foetal calf serum |
| HEPES | 4-(2-hydroxyethyl)-1-piperazine-ethyl sulfonic acid |
| SmGM | The smooth muscle cell substratum |
| Tris-HCl | 2-amino-2-(hydroxymethyl)-1, the ammediol hydrochloride |
| UtSMC | The uterine smooth muscle cell |
B-1. via genetic expression indirect measurement adenosine antagonism
Reporter gene tectosome (CRE luciferase) and cDNA stable transfection immortal cell line CHO K1(Chinese hamster ovary with Adenosine Receptors hypotype A2a or A2b) cell.A2a or A2b acceptor via G α s albumen coupling to adenylate cyclase.By receptor activation, therefore the activation adenylate cyclase, improves the cAMP level in the cell.Via this report gene structure body (a kind of cAMP-dependent form promotor), the variation of cAMP level is combined with luciferase expression.
In order to measure the adenosine antagonism on the Adenosine Receptors hypotype A1, stable transfection CHO K1 cell once more, but use Ca specifically
2+-responsive reporter gene tectosome (NFAT-TA-Luc; Clontech) and A1-G α 16 fusion constructs bodies.Be different from natural A 1 acceptor (G α i-coupling), this receptor chimera body is coupled on the Phospholipase C.At this according to cytosol Ca
2+The concentration expressing luciferase.
At DMEM/F12-Glutamax (Cat.No. 31331-028; Gibco) middle with 10% FCS(foetal calf serum) and various additive (10 milliliters/(Cat.No. 15630 to rise 1M HEPES; Gibco), 14 milliliters/rise MEM Sodium.alpha.-ketopropionate (Cat.No. 11360-039; Gibco)) under 5% carbonic acid gas, cultivate immortal cell line under 37 ℃, and dividing twice weekly.
In order in 384 holes and 96 orifice plate forms, to test, cell with the sowing of 2000 or 5000 cells/well 25 or 50 microlitre test mediums (OptiMEM-Glutamax that contains the FCS that 2.5% activated carbon treatment crosses, Hyclone) in and under 5% carbonic acid gas, cultivating under 37 ℃ until substance testing.At substance testing preceding 24 hours, containing the FCS(Hyclone that 2.5% activated carbon treatment is crossed) OptiMEM in sowing A2a and A2b cell.At substance testing preceding 48 hours, sowing A1-G α 16 cells in the OptiMEM-Glutamax that contains FCS that 2.5% activated carbon treatment crosses and additive.With material with 1 x 10
-5M to 1 x 10
-11The ultimate density of M is inhaled and is moved on in the test medium, and the DMSO content on the cell is no more than 0.5%.Use ultimate density be 30 nM(its roughly be equivalent to EC
50Concentration) NECA(5-N-ethyl-carboxamido-adenosine) as the agonist of A2a and A2b cell.Use 25 nM CPA(N6-UK 80882) (it roughly is equivalent to EC
75Concentration) as the agonist of A1-Ga16 cell.After adding these materials, cell plate were being cultivated 3-4 hour under 5% carbonic acid gas under 37 ℃.In facing measurement forward direction cell, add 50 microlitres subsequently by 50% cytolysis reagent (Triton buffer reagent, PAA Cat.No. T21-160) and the solution that constitutes of 50% luciferase substrate solution (2.5 mM ATP, 0.5 mM fluorescein, 0.1 mM coenzyme A, 10 mM Wheat flavones, 1.35 mM sal epsom, 15 mM DTT, pH 7.8).Detect uciferase activity with luminous reader.Measure IC
50Value, the luciferase that is about to each agonist generation responds the concentration that suppresses to 50% o'clock.Calculate IC with computer program GraphPad PRISM (Version 3.02)
50Value.Use ZM241385(to be used for A2a and A2b cell) and DPCPX(1,3-dipropyl-8-cyclopentyl xanthine) (being used for A1-G α 16 cells) as the benchmark antagonist.
| The embodiment numbering | IC50 A1 [nM] | IC50 A2a [nM] | IC50 A2b [nM] |
| 2 | 1 | >10000 | >10000 |
| 6 | 9.5 | > 10000 | >10000 |
| 9 | 11.2 | >10000 | >10000 |
| 11 | 11.7 | >10000 | >10000 |
| 13 | 1 | >10000 | >10000 |
| 16 | 1.6 | >10000 | >10000 |
| 20 | 1.9 | >10000 | >10000 |
| 22 | 1 | >10000 | >10000 |
| 27 | 99 | >10000 | >10000 |
| 28 | 19 | ? | ? |
| 31 | 42 | ? | ? |
| 32 | 78 | ? | ? |
| 33 | 0.6 | >10000 | >10000 |
| 36 | 0.7 | >10000 | >10000 |
| 39 | 1 | >10000 | >10000 |
| 43 | 23 | >10000 | >10000 |
| 46 | 8.5 | >10000 | >10000 |
B-2. the combination research on the membrane product of the cell that contains adenosine A 1 receptor
In order to make the cytolemma that contains people's adenosine A 1 receptor, dissolve also differential centrifugation subsequently with stably crossing the Chinese hamster ovary celI (seeing B1) of expressing the A1 acceptor.Binding buffer liquid ((50 mM three-(hydroxymethyl)-aminomethane/1 N hydrochloric acid, 5 mM magnesium chlorides, pH 7.4, contain Ultra Turrax (Jahnke﹠amp; Kunkel, Ika-Werk)) born of the same parents molten after, homogenate was under 4 ℃ under 1000 g centrifugal 10 minutes.Throw aside the gained sediment and with supernatant liquor under 4 ℃ under 20000g centrifugal 30 minutes.Throw aside supernatant liquor, be resuspended in sediment in the binding buffer liquid and be stored under-70 ℃ until in conjunction with test.
For the combination test, at 96-hole screen plate (FC/B glass fibre, Multiscreen Millipore) in, in the binding buffer liquid that has added 0.2 units per ml adenosine deaminase (Sigma) (0.2 milliliter of overall test volume), tried to cultivate 1 nM with 30 –, 300 mcg/ml people cytolemma down at 30 ℃ in the presence of the material
3H-DPCPX(1,3-dipropyl-8-cyclopentyl xanthine) (4.44 TBq/mmol, PerkinElmer) 60 minutes.Removing unconjugated radiant by suction with after stopping cultivation, plate washs with the binding buffer liquid that has added 0.1% bovine serum albumin(BSA), subsequently 40 ℃ of following dryings whole night.(Ultima Gold, PerkinElmer) and at liquid scintillation counter (Microbeta Wallac) go up to measure still onboard radiant to add liquid scintillator subsequently.Non-specific binding is meant the radiant in the presence of 1 μ M DPCPX (Sigma), and be generally the total binding radiant＜25%.Measure binding data (IC50 and dissociation constant Ki) by program GraphPad Prism Version 4.0.
B-3. be used to detect the in vivo test of cardiovascular effect: the blood pressure measurement of anesthetized rat
With the male Wistar rat anesthesia of thiopental (100 mg/kg i.p.) with body weight 300-350 gram.At the tracheotomy postoperative, in femoral artery, insert the conduit that is used to measure blood pressure.Tried material with the solution form by the stomach tube oral administration or through femoral vein at intravenous administration (people Br. J. Pharmacol. 2002 such as Stasch; 135:344-355).
B-4. be used to detect cardiovascular effect
In the bodyTest: the blood pressure measurement of clear-headed spontaneous hypertensive rat
The blood pressure measurement of following clear-headed rat uses from DATA SCIENCES INTERNATIONAL DSI, the commercially available telemetering system of USA company.
This system is made of 3 major partss:
1. implantable projector (Physiotel telemetry transmitter)
2. receptor (Physiotel receptor), its through traffic pilot (DSI Data Exchange Matrix) connect to
3. data acquisition computer
This telemetry equipment provides the continuous recording of blood pressure, heart rate and the body movement of clear-headed animal in the environment that they are familiar with.
Animal material
In body weight〉study on adult female, the spontaneous hypertensive rat (SHR Okamoto) of 200 grams.Okamoto Kyoto School of Medicine, the female rats hybridization SHR/NCrl that 1963 male Wistar Kyoto rats of greatly being improved by blood pressure and blood pressure improve slightly and leaving among the F13 of U.S. National Institutes of Health.
After projector is implanted, animal subject is raised in Type 3 Macrolon cages separately.They can arbitrarily obtain standard feed and water.
In the morning 6:00 h and night 19:00 h change circadian rhythm in the laboratory by interior lighting.
Projector is implanted
Before they are used for initial test at least 14 days, in animal subject under aseptic condition the used telemetry transmitter TA11 PA – C40 of operation implantation.Wound healing and implant grow good after, this animal that has instrument can be used repeatedly.
In order to implant, scrape hair and sterilization with the fasting Animal Anesthesia and on the wide area of the outside of belly with Sodital (Nembutal, Sanofi:50 mg/kg i.p.).After opening the abdominal cavity along white line, in descending aorta, insert above the branch point of skull bone this system the liquid filling measuring guide and with tissue adhesive (VetBonD TM, 3M) fixing.Launcher shell is fixed on the musculature of stomach wall at intraperitoneal and closure of wound successively.
After the operation, adopt antibiotic prophylaxis to infect (Tardomyocel COMP Bayer 1 ml/kg s.c.).
Material and solution
Unless describe separately, tried material and give a treated animal (n=6) by the stomach tube per os in each case.Corresponding to the consumption of 5 ml/kg body weight, will be tried substance dissolves in suitable solvent mixture or be suspended among 0.5% Tylose.
One treated animal of use solvent treatment in contrast.
Testing sequence
Be that 24 animals construct this telemetering system.Each trial sheet is (TYear Month Day) under test number.
Distribute to its special-purpose receiving antenna of the rat that respectively has instrument of living in this device (1010 Receiver, DSI).
The receptor of implanting can be by built-in magnetic switch from outer activation.To the process of this test, they are switched to emission in starting.(Dataquest TM A.R.T. is at WINDOWS, and DSI) signal of online record emission is also processed on demand can to pass through data collecting system.Data storing is in folder, and it opens in each case for this reason, and has test number.
In standard program, measured in each case following 10 seconds.
● systolic blood pressure (SBP)
● diastolic blood pressure (DBP)
● mean arterial pressure (MAP)
● heart rate (HR)
● motility (ACT)
Under computer control 5 minutes to serve as duplicate record observed value at interval.In chart with the actual air pressure that records (Ambient Pressure Reference Monitor; APR-1) correction is confirmed as the source data of absolute value and saves as independent data.Further ins and outs are found in the detailed file (DSI) from manufacturers.
Unless describe separately, use at a test day 09:00 h and tried material.After using, measured above-mentioned parameter 24 hours.
Evaluation and test
When off-test, each independent data of gained is classified with analysis software (DATAQUEST TM A.R.T. TM ANALYSIS).Get and use preceding two hours, so that the selected data collection covered from the period of h to the second day the 09:00 h of 07:00 of test day as blank.
Transfer in the storage medium by mean value mensuration (15 minutes mean value) smoothed data and as text in the predeterminable time.The observed value of presorting and compress transferred in the Excel template and with tabulated form present.The gained data storing of each test day is the file of oneself, and it has test number.Result and testing sequence are filed with paper spare form in folder, with digital sort.
B-5. be used to detect cardiovascular effect
In the bodyTest: the diuresis research of the clear-headed rat in the metabolic cage
Wistar rat (200-400 restrains body weight) is raised under the situation that can arbitrarily obtain feed (Altromin) and tap water.In process of the test, animal placed separately in the rat metabolic cage (from Tecniplast Deutschland GmbH, D-82383 Hohenpei enberg) that is fit to this body weight classification 4 hours, can arbitrarily obtain tap water.Being tried material sends in the stomach or intravenous administration by the stomach tube per os in the suitable solvent of 1 to 2 ml/kg body weight.The animal of served as control is only accepted solvent by the respective application approach.Carry out the test of controlled trial and material parallel on the same day.Control group and dosages of substance group contain 4 to 8 animals in each case.In process of the test, animal excretory urine is collected in continuously in the collection container of cage bottom.For each animal, measure the concentration that in urine excretory sodium or potassium ion are measured in the volume of urine of time per unit and the standard method by flame photometry separately.In order to obtain the capacity urine, when on-test, supply the water (common 10 ml/kg body weight) of specified amount to animal by stomach tube.In the body weight of measuring each animal before on-test and after off-test.
B-6. be used to detect cardiovascular effect
In the bodyTest: tried the effect of material in the acute renal failure of glycerine-bring out
Wistar rat (200-320 restrains body weight) stable breeding under the situation that can arbitrarily obtain feed (Altromin) and tap water.In each test, use the rat that the age equates, under light etherization by two back legs all intramuscular injection glycerine-water mixture (volumetric mixture ratio 1:1, volume injected 10 ml/kg) bring out acute renal failure.In addition, the time point (common 14 to 24 hours) of stop supplies tap water can influence the seriousness of renal failure before glycerine injection.Being tried material sends in the stomach or intravenous administration by the stomach tube per os in the suitable solvent of 1 to 2 ml/kg body weight.The animal of served as control is only accepted solvent by the respective application approach.Carry out the test of controlled trial and material parallel on the same day.Control group and dosages of substance group contain 8 to 12 animals in each case.In test, research is simultaneously accepted etherization and solvent simultaneously but is not accepted the rat control group of the same age of intramuscular glycerine injection.After applying this material or applying solvent, rat is placed separately in the metabolic cage (from Tecniplast Deutschland GmbH, D-82383 Hohenpei enberg).Injected back first day and second day collection urine at glycerine, continue 24 hours.Measure the content of sodium, potassium, uric acid and creatinine in the urine.When finishing, the urine collecting phase obtains blood to measure urea, creatinine, uric acid and sodium in each case by the puncture of the retroorbital under gentle etherization or by cardiocentesis (injecting back 48 hours) at glycerine.Sodium or potassium ion.Sodium and potassium ion are measured in standard method by flame photometry.By standard enzyme process and biochemical determination creatinine, urea and uric acid.
B-7. be used to detect cardiovascular effect
In the bodyTest: the research of the chronic renal failure rat that 5/6 nephrectomy is brought out
Checking is tried the kidney provide protection of material in 5/6 nephrectomy (chronic renal failure) rat.These rats are with the feature that develops into of renal glomerulus ultrafiltration and carrying out property renal failure, and they cause the left ventricular hypertrophy and the core fiberization of latter stage nephropathy and hypertension-induced.In experiment more various groups: Sham-operated control group, 5/6 nephrectomy group and with the 5/6 nephrectomy group of being tried the material treatment.Dosage forms for oral administration is tried material.By removing right kidney fully and upper and lower 1/3 renal insufficiency that brings out via 5/6 nephrectomy by the remaining kidney of colligation in other two all backs.After operation for the second time, rat produces carrying out property renal failure (GFR reduction) and is accompanied by proteinuria and hypertension.Heart is a feature with the uremia hypertensive heart disease.When not having treatment, rat dies from end-apparatus damage (the Kalk P. of latter stage nephropathy or hypertension-induced between 19 weeks and 26 weeks, Godes M., Relle K., Rothkege C.l, Hucke A., Stasch J.P. and Hocher B.:NO-independent activation of soluble guanylate cyclase prevents disease progression in rats with 5/6 nephrectomy.
Brit. J. Pharmacol.2006,148,853-859).In order to collect urine, animal was raised in metabolic cage 24 hours.Measure sodium, potassium, calcium, phosphoric acid salt and protein.In automatic analysis equipment with detection kit measure glucose, CrP(C-reacts peptide), the ALAT(alanine aminotransferase), the ASAT(aspartic transaminase), the serum-concentration of potassium, sodium, calcium, phosphoric acid salt, urea and creatinine.In automatic analysis equipment, use the protein concn in pyrogallol Red molybdenum complex reagent mensuration urine and the serum.Calculate glomerular filtration rate(GFR based on creatinine clearance.Measure systolic blood pressure and heart rate with the tail cover on the clear-headed rat by plethysmography.Measure body weight weekly.With the aldosterone in commercially available radioimmunoassay method plasma renin activity and the urine.When finishing, research kills all rats.Blood sampling is measured glucose, creatinine, urea, liver enzyme, CrP, sodium, serum protein and plasma renin activity.Measure body weight and cardiac weight and kidney weight.
C. the application examples of pharmaceutical composition
Compound of the present invention can followingly change into pharmaceutical preparation:
Tablet:
Form:
(from BASF, Ludwigshafen is Germany) with 2 milligrams of Magnesium Stearates for 100 milligrams of compounds of the present invention, 50 milligrams of lactose (monohydrate), 50 milligrams of W-Gums (natural), 10 milligrams of Polyvinylpyrolidone (PVP)s (PVP 25).
212 milligrams of tablet weight.8 millimeters of diameters, 12 millimeters of convexity radiuses.
Produce:
With the mixture of compound of the present invention, lactose and starch in water with 5% PVP solution (w/w) granulation.After drying, particle was mixed with Magnesium Stearate 5 minutes.Suppress this mixture (, seeing above) with common tabletting machine about the tablet pattern.The pressing force that uses 15 kN is as the compacting standard.
Oral suspension:
Form:
1000 milligrams of compounds of the present invention, 1000 milligrams of ethanol (96%), 400 milligrams of Rhodigel
(from the FMC of company, Pennsylvania, the xanthan gum of USA) and 99 gram water.
10 milliliters of oral suspensions are equivalent to 100 milligrams of compounds of the present invention of single agent.
Produce:
Rhodigel is suspended in the ethanol, compound of the present invention is added in this suspension.When stirring, add entry.It was stirred about 6 hours, stop swelling until Rhodigel.
Oral liquid:
Form:
500 milligrams of compounds of the present invention, 2.5 gram tweens and 97 gram poly(oxyethylene glycol) 400.20 gram oral liquids are equivalent to 100 milligrams of compounds of the present invention of single agent.
Produce:
Under agitation compound of the present invention is suspended in the mixture of polyoxyethylene glycol and tween.Continuing stirring operation dissolves fully until compound of the present invention.
I.v. solution:
Compound of the present invention is dissolved in the compatible solvent of physiology (for example isoosmotic customary salt solution, 5% glucose solution and/or 30% PEG, 400 solution) with the concentration that is lower than saturation solubility.This solution is imposed sterile filtration and is contained in the aseptic and apyrogenic injection vessel.
Claims (13)
1. the solvate of the compound of formula (I) and their salt, solvate and this salt
Wherein
Q represents phenyl or pyridyl,
R
1Represent hydrogen, cyano group, (C
1-C
3)-alkyl, trifluoromethyl, (C
1-C
3)-alkoxyl group or trifluoromethoxy,
R
2Represent phenyl, naphthyl or 5-or 6-unit heteroaryl,
Wherein phenyl, naphthyl and 5-or 6-unit heteroaryl can be independently from each other halogen, cyano group, (C by 1 or 2
1-C
4)-alkyl, single methyl fluoride, difluoromethyl, trifluoromethyl, (C
1-C
4The substituting group of)-alkoxyl group, single fluorine methoxyl group, difluoro-methoxy and trifluoromethoxy replaces,
R
3Representation hydroxy carbonyl, aminocarboxyl, cyano group aminocarboxyl, (C
1-C
4)-alkyl sulfonyl-amino carbonyl,
Bisoxazoline ketone group or tetrazolium-5-base,
Wherein
The bisoxazoline ketone group can be replaced by methyl substituents,
R
4Represent hydrogen, halogen, (C
1-C
4)-alkyl, single methyl fluoride, difluoromethyl, trifluoromethyl, (C
1-C
4)-alkoxyl group, single fluorine methoxyl group, difluoro-methoxy or trifluoromethoxy,
R
5Represent hydrogen, halogen, (C
1-C
4)-alkyl, single methyl fluoride, difluoromethyl, trifluoromethyl, (C
1-C
4)-alkoxyl group, single fluorine methoxyl group, difluoro-methoxy or trifluoromethoxy,
R
6Represent the group of following formula
Wherein
* be meant the tie point with this pyrazoles,
Ring U represents phenyl, pyridyl, pyrimidyl or pyrazinyl,
Wherein phenyl, pyridyl, pyrimidyl and pyrazinyl can be independently from each other halogen, (C by 1 to 3
1-C
4)-alkyl, trifluoromethyl, hydroxyl, (C
1-C
4The substituting group of)-alkoxyl group and trifluoromethoxy replaces,
Wherein at the (C of these parts
1-C
4)-alkyl and (C
1-C
4)-alkoxyl group can be independently from each other hydroxyl and (C by 1 or 2
1-C
4The substituting group of)-alkoxyl group replaces,
And
Ring V
1Representative is fused to the benzyl ring on the ring U or is fused to 5-or the 6-unit heteroaryl ring that encircles on the U,
Wherein said benzyl ring and described 5-or 6-unit heteroaryl ring can be independently from each other halogen, cyano group, (C by 1 to 4
1-C
4)-alkyl, trifluoromethyl, (C
1-C
4)-alkoxyl group, trifluoromethoxy, (C
1-C
4)-alkyl-carbonyl, amino, list-(C
1-C
4)-alkylamino and two-(C
1-C
4The substituting group of)-alkylamino replaces.
2. the solvate of the compound of the formula described in claim 1 (I) and their salt, solvate and this salt, wherein
Q represents phenyl,
R
1Represent hydrogen, methyl or trifluoromethyl,
R
2Represent phenyl,
Wherein phenyl can be replaced by 1 or 2 substituting group that is independently from each other fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxyl group, oxyethyl group and trifluoromethoxy,
R
3The representation hydroxy carbonyl,
R
4Represent hydrogen, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxyl group, oxyethyl group, difluoro-methoxy or trifluoromethoxy,
R
5Represent hydrogen,
R
6Represent the group of following formula
Wherein
* be meant the tie point with this pyrazoles,
A
1Represent CR
10Or N,
Wherein
R
10Represent hydrogen, fluorine, chlorine or methyl,
A
2Represent CR
11Or N,
Wherein
R
11Represent hydrogen, fluorine, chlorine or methyl,
A
3Represent CR
12Or N,
Wherein
R
12Represent hydrogen, fluorine, chlorine, methyl or methoxy,
A
4Represent CR
13Or N,
Wherein
R
13Represent hydrogen, fluorine, chlorine, methyl or methoxy,
D
1Represent CR
15Or N,
Wherein
R
15Represent hydrogen, fluorine, chlorine or methyl,
D
2Represent CR
16Or N,
Wherein
R
16Represent hydrogen, fluorine, chlorine or methyl,
D
3Represent CR
17Or N,
Wherein
R
17Represent hydrogen, fluorine, chlorine or methyl,
D
4Represent CR
18Or N,
Wherein
R
18Represent hydrogen, fluorine, chlorine or methyl,
D
5Represent NR
19, O or S,
Wherein
R
19Represent hydrogen or methyl,
Condition is group D
1, D
2, D
3, D
4And D
5In at least one represent N or NR
19,
E
1Represent CR
21Or N,
Wherein
R
21Represent hydrogen, fluorine, chlorine or methyl,
E
2Represent CR
22Or N,
Wherein
R
22Represent hydrogen, fluorine, chlorine or methyl,
E
3Represent CR
23Or N,
Wherein
R
23Represent hydrogen, fluorine, chlorine, methyl or amino,
E
4Represent CR
24Or N,
Wherein
R
24Represent hydrogen, fluorine, chlorine or methyl,
Condition is group E
2, E
3And E
4In maximum two represent N,
G
1Represent CR
26Or N,
Wherein
R
26Represent hydrogen, fluorine, chlorine or methyl,
G
2Represent CR
27Or N,
Wherein
R
27Represent hydrogen, fluorine, chlorine or methyl,
G
3Represent CR
28Or N,
Wherein
R
28Represent hydrogen, fluorine, chlorine, methyl or amino,
G
4Represent CR
29Or N,
Wherein
R
29Represent hydrogen, fluorine, chlorine or methyl,
Condition is a group G
2, G
3And G
4In maximum two represent N,
K
1Represent CR
35Or N,
Wherein
R
35Represent hydrogen, fluorine, chlorine or methyl,
L
1Represent CR
41Or N,
Wherein
R
41Represent hydrogen, fluorine, chlorine or methyl,
R
7Represent hydrogen, fluorine, chlorine, methyl, hydroxyl, methoxy or ethoxy,
R
8Represent hydrogen, fluorine, chlorine, methyl or methoxy,
R
9Represent hydrogen, fluorine, chlorine, methyl, methoxyl group, amino, methylamino or dimethylamino,
R
14Represent hydrogen, fluorine, chlorine, methyl, hydroxyl, methoxy or ethoxy,
R
20Represent hydrogen, fluorine, chlorine, methyl, hydroxyl, methoxy or ethoxy,
R
25Represent hydrogen, fluorine, chlorine, methyl, hydroxyl, methoxy or ethoxy,
R
30Represent hydrogen, fluorine, chlorine, methyl, hydroxyl, methoxy or ethoxy,
R
31Represent hydrogen, fluorine, chlorine or methyl,
R
32Represent hydrogen, fluorine, chlorine or methyl,
R
33Represent hydrogen, fluorine, chlorine, methyl or amino,
R
34Represent hydrogen, fluorine, chlorine, methyl, methoxyl group, amino, methylamino or dimethylamino,
R
36Represent hydrogen, fluorine, chlorine, methyl, hydroxyl, methoxy or ethoxy,
R
37Represent hydrogen, fluorine, chlorine or methyl,
R
38Represent hydrogen, fluorine, chlorine, methyl, methoxyl group, amino, methylamino or dimethylamino,
R
39Represent hydrogen, fluorine, chlorine, methyl or amino,
And
R
40Represent hydrogen, fluorine, chlorine or methyl.
3. the solvate of the compound of the formula described in claim 1 (I) and their salt, solvate and this salt, wherein
Q represents phenyl,
R
1Represent hydrogen, cyano group, methyl, ethyl or trifluoromethyl,
R
2Represent phenyl,
Wherein phenyl can be independently from each other fluorine, chlorine, (C by 1 or 2
1-C
4)-alkyl, trifluoromethyl, (C
1-C
4The substituting group of)-alkoxyl group and trifluoromethoxy replaces,
R
3Representation hydroxy carbonyl or methyl sulphonyl aminocarboxyl,
R
4Represent hydrogen, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxyl group, oxyethyl group, difluoro-methoxy or trifluoromethoxy,
R
5Represent hydrogen, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxyl group, oxyethyl group, difluoro-methoxy or trifluoromethoxy,
R
6Represent the group of following formula
Wherein
* be meant the tie point with this pyrazoles,
A
1Represent CR
10Or N,
Wherein
R
10Represent hydrogen, fluorine, chlorine or methyl,
A
2Represent CR
11Or N,
Wherein
R
11Represent hydrogen, fluorine, chlorine or methyl,
A
3Represent CR
12Or N,
Wherein
R
12Represent hydrogen, fluorine, chlorine or methyl,
A
4Represent CR
13Or N,
Wherein
R
13Represent hydrogen, fluorine, chlorine or methyl,
D
1Represent CR
15Or N,
Wherein
R
15Represent hydrogen, fluorine, chlorine or methyl,
D
2Represent CR
16Or N,
Wherein
R
16Represent hydrogen, fluorine, chlorine or methyl,
D
3Represent CR
17Or N,
Wherein
R
17Represent hydrogen, fluorine, chlorine or methyl,
D
4Represent CR
18Or N,
Wherein
R
18Represent hydrogen, fluorine, chlorine or methyl,
D
5Represent NR
19, O or S,
Wherein
R
19Represent hydrogen or methyl,
E
1Represent CR
21Or N,
Wherein
R
21Represent hydrogen, fluorine, chlorine or methyl,
E
2Represent CR
22Or N,
Wherein
R
22Represent hydrogen, fluorine, chlorine or methyl,
E
3Represent CR
23Or N,
Wherein
R
23Represent hydrogen, fluorine, chlorine or methyl,
E
4Represent CR
24Or N,
Wherein
R
24Represent hydrogen, fluorine, chlorine or methyl,
Condition is group E
2, E
3And E
4In maximum two represent N,
G
1Represent CR
26Or N,
Wherein
R
26Represent hydrogen, fluorine, chlorine or methyl,
G
2Represent CR
27Or N,
Wherein
R
27Represent hydrogen, fluorine, chlorine or methyl,
G
3Represent CR
28Or N,
Wherein
R
28Represent hydrogen, fluorine, chlorine or methyl,
G
4Represent CR
29Or N,
Wherein
R
29Represent hydrogen, fluorine, chlorine or methyl,
Condition is G
2, G
3And G
4In maximum two represent N,
R
7Represent hydrogen, fluorine, chlorine or methyl,
R
8Represent hydrogen, fluorine, chlorine or methyl.
R
9Represent hydrogen, fluorine, chlorine or methyl,
R
14Represent hydrogen, fluorine, chlorine or methyl,
R
20Represent hydrogen, fluorine, chlorine or methyl,
And
R
25Represent hydrogen, fluorine, chlorine or methyl.
4. the compound of the formula (I) described in claim 1 or 3 and the solvate of their salt, solvate and this salt, wherein
Q represents the group of following formula
Wherein
# is meant the tie point amino with this,
R
3The representation hydroxy carbonyl,
R
4Represent hydrogen, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxyl group, difluoro-methoxy or trifluoromethoxy,
R
5Represent hydrogen or fluorine,
R
1Represent hydrogen or methyl,
R
2Represent phenyl,
Wherein phenyl can be replaced by 1 or 2 substituting group that is independently from each other fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxyl group, oxyethyl group or trifluoromethoxy,
R
6Represent the group of following formula
Wherein
* be meant the tie point with this pyrazoles,
A
1Represent CR
10Or N,
Wherein
R
10Represent hydrogen, fluorine, chlorine or methyl,
R
7Represent hydrogen, fluorine, chlorine or methyl,
R
11Represent hydrogen, fluorine, chlorine or methyl.
5. the compound of the formula (I) described in claim 1 or 2 and the solvate of their salt, solvate and this salt, wherein
Q represents the group of following formula
Wherein
# is meant the tie point amino with this,
R
3The representation hydroxy carbonyl,
R
4Represent hydrogen, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxyl group, difluoro-methoxy or trifluoromethoxy,
R
5Represent hydrogen,
R
1Represent methylidene,
R
2Represent the group of following formula
Wherein
The tie point of ## representative and this pyrazoles,
R
42Represent hydrogen, fluorine, chlorine, trifluoromethyl, methyl, ethyl, methoxy or ethoxy,
R
43Represent hydrogen, fluorine, chlorine or methyl,
R
6Represent the group of following formula
Wherein
* be meant the tie point with this pyrazoles,
A
1Represent CR
10Or N,
Wherein
R
10Represent hydrogen, fluorine or chlorine,
A
2Represent CR
11,
Wherein
R
11Represent hydrogen, fluorine, chlorine or methyl,
A
3Represent N,
A
4Represent N,
E
1Represent CR
21,
Wherein
R
21Represent hydrogen,
E
2Represent N,
E
3Represent CR
23,
Wherein
R
23Represent hydrogen or amino,
E
4Represent N,
G
1Represent CR
26,
Wherein
R
26Represent hydrogen,
G
2Represent N,
G
3Represent CR
28,
Wherein
R
28Represent hydrogen or amino,
G
4Represent N,
K
1Represent N,
R
7Represent hydrogen, fluorine, chlorine, methyl, methoxy or ethoxy,
R
8Represent hydrogen,
R
9Represent hydrogen,
R
20Represent hydrogen, fluorine, chlorine, methyl, methoxy or ethoxy,
R
25Represent hydrogen, fluorine, chlorine, methyl, methoxy or ethoxy,
R
30Represent hydrogen, fluorine, chlorine, methyl, methoxy or ethoxy,
R
31Represent hydrogen, fluorine or chlorine,
R
32Represent hydrogen, fluorine or chlorine,
R
33Represent hydrogen,
And
R
34Represent hydrogen.
6. the manufacture method of the compound of the formula described in claim 1 to 5 (I) is characterized in that,
The compound of [A] formula (II)
R wherein
1And R
2Have the implication that provides in the claim 1 to 5 in each case,
In inert solvent, transform the compound of an accepted way of doing sth (III-A) with halogenating agent
R wherein
1And R
2Has the implication that provides in the claim 1 to 5 in each case
And
X
1Represent halogen, particularly represent bromine or iodine,
Its subsequently in inert solvent in the presence of alkali and suitable palladium catalyst with the reaction of the compound of formula (IV)
R wherein
6Has the implication that provides in the claim 1 to 5
And
T
1Represent hydrogen or two residue T
1Formation-C (CH together
3)
2-C (CH
3)
2-Huo – CH
2C (CH
3)
2CH
2-bridge,
To form the compound of formula (V-A)
R wherein
1, R
2And R
6Have the implication that provides in the claim 1 to 5 in each case,
And its subsequently in inert solvent in the presence of appropriate catalyst with the reaction of the compound of formula (VI-A)
Wherein Q, R
4And R
5Has the implication that provides in the claim 1 to 5 in each case
And
T
2Representative (C
1-C
4)-alkyl,
X
2Represent halogen, preferred bromine,
To form the compound of formula (VII)
Wherein Q, T
2, R
1, R
2, R
4, R
5And R
6Have the above implication of regulation in each case,
Or
The compound of [B] formula (II) in inert solvent in the presence of appropriate catalyst with the reaction of the compound of formula (VI-A) to form the compound of formula (III-B)
Wherein Q, R
1, R
2, R
4And R
5Have the implication that provides in the claim 1 to 5 in each case,
And
T
2Representative (C
1-C
4)-alkyl,
And it transforms the compound of an accepted way of doing sth (V-B) subsequently with halogenating agent in inert solvent
Wherein Q, T
2, X
1, R
1, R
2, R
4And R
5Have the above implication of regulation in each case,
And
X
1Represent halogen, preferred bromine,
And its subsequently in inert solvent in the presence of alkali and suitable palladium catalyst with the reaction of the compound of formula (IV) forming the compound of formula (VII),
Or
[C] makes the compound of formula (VIII)
R wherein
6Have the implication that provides in the claim 1 to 5 and
X
3Represent halogen, preferred bromine or iodine,
In inert solvent in the presence of suitable palladium catalyst with the trimethyl silyl acetonitrile reaction to form the compound of formula (IX)
R wherein
6Have the implication that provides in the claim 1 to 5,
And its subsequently in inert solvent in the presence of suitable alkali with the reaction of the ester of formula (X)
R wherein
1Have the implication that provides in the claim 1 to 5 and
T
3Representative (C
1-C
4)-alkyl,
To form the compound of formula (XI)
R wherein
1And R
6Has the implication that provides in the claim 1 to 5 in each case
And
Ak
+Represent basic ion, preferred sodium,
And it uses the hydrazine of formula (XII) to transform subsequently
R wherein
2Have the implication that provides in the claim 1 to 5,
The compound of an accepted way of doing sth (V-A), this further reacts the compound that forms formula (VII) according to aforesaid method [A],
And the compound of the formula of Chan Shenging (VII) transforms the carboxylic acid of an accepted way of doing sth (I-1) subsequently by the hydrolysis of this ester in each case
?(I-1),
Wherein Q, R
1, R
2, R
4, R
5And R
6Have the implication that provides in the claim 1 to 5 in each case,
And the compound of gained formula (I-1) is optional with (i) solvent and/or (ii) alkali or the sour solvate that changes into their solvate, salt and/or this salt accordingly.
7. the compound of the formula described in one of claim 1 to 5 (I) is used for the treatment of and/or preventing disease.
8. the compound of the formula described in one of claim 1 to 5 (I), be used for acute mistake compensatory and chronic heart failure, hypervolemia and etc. the method that treats and/or prevents of capacity hyponatremia, liver cirrhosis, ascites, oedema, ephrosis, acute and chronic renal failure, renal insufficiency and syndrome of inappropriate ADH secretion (SIADH).
The compound of the formula described in one of claim 1 to 5 (I) be used for making treat and/or prevent acute mistake compensatory and chronic heart failure, hypervolemia and etc. the purposes of medicine of capacity hyponatremia, liver cirrhosis, ascites, oedema, ephrosis, acute and chronic renal failure, renal insufficiency and syndrome of inappropriate ADH secretion (SIADH) usefulness.
10. medicine contains just like the compound of the formula described in one of claim 1 to 5 (I) and inertia, nontoxic, pharmaceutically acceptable vehicle.
11. medicine contains compound and one or more other active substances that is selected from diuretic(s), Angiotensin AII antagonist, ACE inhibitor, beta-blocker, mineralocorticoid receptor antagonists, organic nitrate, NO donor, guanylate cyclase stimulant, guanylate cyclase activators, vasopressin antagonists and has the material of positive inotropic action just like the formula described in one of claim 1 to 5 (I).
12. the medicine described in claim 10 or 11, be used for the treatment of and/or prophylaxis of acute lose compensatory and chronic heart failure, hypervolemia and etc. capacity hyponatremia, liver cirrhosis, ascites, oedema, ephrosis, acute and chronic renal failure, renal insufficiency and syndrome of inappropriate ADH secretion (SIADH).
13. use the compound of at least a formula (I) described in one of claim 1 to 5 of significant quantity or acute mistake compensatory that at least a medicine described in one of claim 10 to 12 treats and/or prevents humans and animals and chronic heart failure, hypervolemia and etc. the method for capacity hyponatremia, liver cirrhosis, ascites, oedema, ephrosis, acute and chronic renal failure, renal insufficiency and syndrome of inappropriate ADH secretion (SIADH).
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102008039083A DE102008039083A1 (en) | 2008-08-21 | 2008-08-21 | Substituted 5-aminopyrazoles and their use |
| DE102008039083.6 | 2008-08-21 | ||
| PCT/EP2009/005810 WO2010020363A1 (en) | 2008-08-21 | 2009-08-11 | Substituted 5-aminopyrazoles and use thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102197031A true CN102197031A (en) | 2011-09-21 |
Family
ID=41100577
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009801418695A Pending CN102197031A (en) | 2008-08-21 | 2009-08-11 | Substituted 5-aminopyrazoles and use thereof |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US20100099681A1 (en) |
| EP (1) | EP2321296A1 (en) |
| JP (1) | JP2012500236A (en) |
| KR (1) | KR20110042082A (en) |
| CN (1) | CN102197031A (en) |
| AR (1) | AR073064A1 (en) |
| CA (1) | CA2734787A1 (en) |
| DE (1) | DE102008039083A1 (en) |
| TW (1) | TW201022225A (en) |
| UY (1) | UY32052A (en) |
| WO (1) | WO2010020363A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114773333A (en) * | 2021-12-25 | 2022-07-22 | 上海泰坦科技股份有限公司 | Synthesis method of halogenated triazolopyridine |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP6299591B2 (en) * | 2012-07-03 | 2018-03-28 | 小野薬品工業株式会社 | Compound having somatostatin receptor agonist activity and pharmaceutical use thereof |
| WO2014130241A1 (en) | 2013-02-20 | 2014-08-28 | E. I. Du Pont De Nemours And Company | Fungicidal pyrazoles |
| WO2016092559A1 (en) * | 2014-12-12 | 2016-06-16 | Oat & Iil India Laboratories Private Limited | Substituted pyrazole derivatives having activity as fungicides |
| WO2018052838A1 (en) | 2016-09-16 | 2018-03-22 | E. I. Du Pont De Nemours And Company | Fungicidal pyrazoles |
| EP3538518A1 (en) | 2016-11-08 | 2019-09-18 | Merck Patent GmbH | Substituted quinoxaline derivatives as inhibitors of pfkfb |
| EP3354645A1 (en) * | 2017-01-26 | 2018-08-01 | Patheon Austria GmbH & Co KG | Process for preparing urolithins |
| WO2019168972A1 (en) | 2018-02-27 | 2019-09-06 | Amazentis Sa | Process-scale synthesis of urolithin a |
| TW202400547A (en) | 2018-09-06 | 2024-01-01 | 美商富曼西公司 | Fungicidal nitroanilino substituted pyrazoles |
| US20230086702A1 (en) | 2019-04-18 | 2023-03-23 | The Johns Hopkins University | Substituted 2-amino-pyrazolyl-[1,2,4]triazolo[1,5a]pyridine derivatives and use thereof |
| TW202200012A (en) | 2020-03-11 | 2022-01-01 | 美商富曼西公司 | Fungicidal mixtures |
| CN113372200B (en) * | 2021-07-12 | 2022-04-19 | 无锡双启科技有限公司 | Preparation method of 2-bromo-6-fluoroanisole |
Family Cites Families (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5201938A (en) | 1991-07-19 | 1993-04-13 | Dowelanco | N-pyrazolyl-1,2,4-triazolo[1,5-c]pyrimidine-2-sulfonamide herbicides |
| JPH07500116A (en) | 1992-03-26 | 1995-01-05 | ダウエランコ | N-heterocyclic nitroanilines as fungicides |
| US5541213A (en) * | 1993-06-24 | 1996-07-30 | Eisai Co., Ltd. | Propenoic acid derivatives diazole propenoic acid compounds which have useful pharmaceutical utility |
| JPH07285962A (en) | 1994-04-20 | 1995-10-31 | Nissan Chem Ind Ltd | Pyridinecarboxylic acid amide derivative |
| DE19834044A1 (en) | 1998-07-29 | 2000-02-03 | Bayer Ag | New substituted pyrazole derivatives |
| DE19834047A1 (en) | 1998-07-29 | 2000-02-03 | Bayer Ag | Substituted pyrazole derivatives |
| DE19943636A1 (en) | 1999-09-13 | 2001-03-15 | Bayer Ag | Novel dicarboxylic acid derivatives with pharmaceutical properties |
| DE19943634A1 (en) | 1999-09-13 | 2001-04-12 | Bayer Ag | Novel dicarboxylic acid derivatives with pharmaceutical properties |
| DE19943639A1 (en) | 1999-09-13 | 2001-03-15 | Bayer Ag | Dicarboxylic acid derivatives with novel pharmaceutical properties |
| DE19943635A1 (en) | 1999-09-13 | 2001-03-15 | Bayer Ag | Novel aminodicarboxylic acid derivatives with pharmaceutical properties |
| AR031176A1 (en) | 2000-11-22 | 2003-09-10 | Bayer Ag | NEW DERIVATIVES OF PIRAZOLPIRIDINA SUBSTITUTED WITH PIRIDINE |
| DE10110749A1 (en) | 2001-03-07 | 2002-09-12 | Bayer Ag | Substituted aminodicarboxylic acid derivatives |
| DE10110750A1 (en) | 2001-03-07 | 2002-09-12 | Bayer Ag | Novel aminodicarboxylic acid derivatives with pharmaceutical properties |
| DE10220570A1 (en) | 2002-05-08 | 2003-11-20 | Bayer Ag | Carbamate-substituted pyrazolopyridines |
| UY27967A1 (en) | 2002-09-10 | 2004-05-31 | Pfizer | 2-HINDROXI-1,3-DIAMINOALCANE OIL |
| AR042067A1 (en) | 2002-11-27 | 2005-06-08 | Bayer Pharmaceuticals Corp | USEFUL ANILINOPIRAZOL DERIVATIVES IN THE TREATMENT OF DIABETES |
| ATE410168T1 (en) * | 2003-07-22 | 2008-10-15 | Cv Therapeutics Inc | A1 ADENOSINE RECEPTOR ANTAGONISTS |
| AR049418A1 (en) * | 2004-02-27 | 2006-08-02 | Bayer Pharmaceuticals Corp | DERIVATIVES OF HETEROARILAMINOPIRAZOL AND PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF DIABETES. |
| US20080009531A1 (en) | 2004-05-20 | 2008-01-10 | Bayer Pharmaceuticals Corporation | 5-Anilino-4-Heteroarylpyrazole Derivatives Useful for the Treatment of Diabetes |
| US7696210B2 (en) | 2004-06-17 | 2010-04-13 | Wyeth | Gonadotropin releasing hormone receptor antagonists |
| EP1928455A1 (en) | 2005-08-31 | 2008-06-11 | Bayer Healthcare, LLC | Anilinopyrazole derivatives useful for the treatment of diabetes |
| AU2007273057A1 (en) | 2006-07-12 | 2008-01-17 | Merck Sharp & Dohme Corp. | Substituted pyrazoles as ghrelin receptor antagonists |
| JP2010500372A (en) | 2006-08-09 | 2010-01-07 | スミスクライン ビーチャム コーポレーション | Novel compounds as antagonists or inverse agonists for opioid receptors |
-
2008
- 2008-08-21 DE DE102008039083A patent/DE102008039083A1/en not_active Withdrawn
-
2009
- 2009-08-11 EP EP09777798A patent/EP2321296A1/en not_active Withdrawn
- 2009-08-11 JP JP2011523333A patent/JP2012500236A/en active Pending
- 2009-08-11 WO PCT/EP2009/005810 patent/WO2010020363A1/en active Application Filing
- 2009-08-11 CN CN2009801418695A patent/CN102197031A/en active Pending
- 2009-08-11 KR KR1020117003762A patent/KR20110042082A/en not_active Application Discontinuation
- 2009-08-11 CA CA2734787A patent/CA2734787A1/en not_active Abandoned
- 2009-08-13 US US12/540,657 patent/US20100099681A1/en not_active Abandoned
- 2009-08-14 UY UY0001032052A patent/UY32052A/en not_active Application Discontinuation
- 2009-08-14 AR ARP090103152A patent/AR073064A1/en unknown
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114773333A (en) * | 2021-12-25 | 2022-07-22 | 上海泰坦科技股份有限公司 | Synthesis method of halogenated triazolopyridine |
Also Published As
| Publication number | Publication date |
|---|---|
| EP2321296A1 (en) | 2011-05-18 |
| KR20110042082A (en) | 2011-04-22 |
| AR073064A1 (en) | 2010-10-13 |
| DE102008039083A1 (en) | 2010-02-25 |
| JP2012500236A (en) | 2012-01-05 |
| WO2010020363A1 (en) | 2010-02-25 |
| TW201022225A (en) | 2010-06-16 |
| UY32052A (en) | 2010-03-26 |
| US20100099681A1 (en) | 2010-04-22 |
| CA2734787A1 (en) | 2010-02-25 |
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